This invention relates to a series of enamine derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T. A., Nature, 346, 425, (1990); Springer, T. A., Cell, 76, 301, (1994)]. Specific cell surface molecules collectively referred to as cell adhesion molecules mediate many of these interactions.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 16 different integrin alpha chains and 8 different integrin beta chains have been identified [Newman, P. et al, Molecular Medicine Today, 304, (1996)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in the field. Thus the integrin xcex14xcex21 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA-4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised to date [Sonnenberg, A., Current Topics in Microbiology and Immunology, 184, 7, (1993)].
The importance of integrin function in normal physiological responses is highlighted by two human deficiency diseases in which integrin function is defective. Thus in the disease termed Leukocyte Adhesion Deficiency (LAD) there is a defect in one of the families of integrins expressed on leukocytes [Marlin, S. D. et al, J. Exp. Med. 164, 855, (1986)]. Patients suffering from this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections, which in extreme cases may be fatal. In the case of patients suffering from the disease termed Glanzman""s thrombasthenia (a defect in a member of the beta 3 integrin family) there is a defect in blood clotting (Hodivala-Dilke, K. M., J. Clin. Invest. 103, 229, (1999)].
The potential to modify integrin function in such a way as to beneficially modulate cell adhesion has been extensively investigated in animal models using specific antibodies and peptides that block various functions of these molecules [e.g. Issekutz, T. B., J. Immunol. 149, 3394, (1992); Li, Z. et al, Am. J. Physiol. 263, L723, (1992); Mitjans, F. et al, J. Cell Sci. 108, 2825, (1995); Brooks, P. C. et al, J. Clin. Invest. 96, 1815, (1995); Binns, R. M. et al, J. Immunol. 157, 4094, (1996); Hammes, H.-P. et al, Nature Medicine 2, 529, (1996); Srivata, S. et al, Cardiovascular Res. 36, 408 (1997)]. A number of monoclonal antibodies which block integrin function are currently being investigated for their therapeutic potential in human disease, and one, ReoPro, a chimeric antibody against the platelet integrin xcex1llbxcex23 is in use as a potent anti-thrombotic agent for use in patients with cardiovascular complications following coronary angioplasty.
Integrins recognize both cell surface and extracellular matrix ligands, and ligand specificity is determined by the particular alpha-beta subunit combination of the molecule [Newman, P., ibid]. One particular integrin subgroup of interest involves the xcex14 chain which can pair with two different beta chains xcex21 and xcex27 [Sonnenberg, A, ibid]. The xcex14xcex21 pairing occurs on many circulating leukocytes (for example lymphocytes, monocytes, eosinophils and basophils) although it is absent or only present at low levels on circulating neutrophils. xcex14xcex21 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L., Cell, 62, 3, (1990)]. The molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J. et al, Ciba Foundation Symposium, 189, 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between xcex14xcex21 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A. et al, Nature, 356, 63, (1992); Podolsky, D. K. et al, J. Clin. Invest. 92, 372, (1993); Abraham, W. M. etal, J. Clin. Invest. 93, 776, (1994)].
The integrin generated by the pairing of xcex14 and xcex27 has been termed LPAM-1 [Holzmann, B. and Weissman, I. L., EMBO J. 8, 1735, (1989)]. The xcex14xcex27 pairing is expressed on certain sub-populations of T and B lymphocytes and on eosinophils [Erle, D. J. et al, J. Immunol. 153, 517 (1994)]. Like xcex14xcex21, xcex14xcex27 binds to VCAM-1 and fibronectin. In addition, xcex1a4xcex27 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al, Cell, 74, 185, (1993)]. The interaction between xcex14xcex27 and MAdCAM-1 may also be important sites of inflammation outside of mucosal tissue [Yang, X.-D. etal, PNAS, 91, 12604, (1994)].
Regions of the peptide sequence recognizeded by xcex14xcex21 and xcex14xcex27 when they bind to their ligands have been identified. xcex14xcex21 seems to recognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al, ibid] whilst xcex14xcex27 recognises a LDT sequence in MAdCAM-1 [Birskin, M. J. et al, J. Immunol. 156, 719, (1996)]. There have been several reports of inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. et al, J. Biol. Chem., 269, 18668, (1994); Shorff, H. N. et al, Biorganic Med. Chem. Lett., 6, 2495, (1996); Vanderslice, P. et al, J. Immunol., 158, 1710, (1997)]. It has also been reported that a short peptide sequence derived from the xcex14xcex21 binding site in fibronectin can inhibit a contact hypersensitivity reaction in a trinitrochlorobenzene sensitised mouse [Ferguson, T. A, et al, PNAS, 88, 8072, (1991)].
Since the alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states. However, because of the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is important to be able to identify selective inhibitors of the alpha 4 subgroup.
We have now found a group of compounds which are potent and selective inhibitors of xcex14 integrins. Members of the group are able to inhibit xcex14 integrins such as xcex14xcex21 and/or xcex14xcex27 at concentrations at which they generally have no or minimal inhibitory action on xcex1 integrins of other subgroups. These compounds possess the additional advantage of good pharmacokinetic properties, especially low plasma clearance.
Thus according to one aspect of the invention we provide a compound of formula (1) 
wherein
R1 is a group Ar1 L2Ar2Alk- in which Ar1 is an optionally substituted aromatic or heteroaromatic group, L2 is a covalent bond or a linker atom or group, Ar2 is an optionally substituted arylene or heteroarylene group and Alk is a chain xe2x80x94CH2xe2x80x94CH(R)xe2x80x94, xe2x80x94CHxe2x95x90C(R)xe2x80x94, 
in which R is a carboxylic acid (xe2x80x94CO2H) or a derivative or biostere thereof;
R2 is a hydrogen atom or a C1-6 alkyl group;
the ring Cy is an unsaturated cycloaliphatic or heterocycloaliphatic ring containing X, in which X is a N atom or a C(Rw) group;
Rw is a group Rz;
Rx which may be present or any available carbon atom of the ring Cy is a oxo (xe2x95x90O), thioxo (xe2x95x90S) or imino (xe2x95x90NR30) group in which R30 is an aliphatic, heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;
m is zero or the integer 1, 2 or 3;
Rz which may be present on any available carbon or nitrogen atom of the ring Cy is selected from a halogen atom or xe2x80x94(Alk4)vL1(Alk1)nR3 in which Alk4 is a straight or branched C1-3alkylene chain, v is zero or the integer 1, L1 is a covalent bond or a linker atom or group, n is zero or the integer 1,
Alk1 is an optionally substituted aliphatic chain and R3 is a hydrogen atom or a xe2x80x94CN, xe2x80x94NO2 or an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, heteropolycycloaliphatic, aromatic or heteroaromatic group;
p is zero or the integer 1, 2, 3 or 4;
provided that Cy is not a cyclobutenedione group;
and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that compounds of formula (1) may have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
Optionally substituted aromatic groups represented by Ar1 when present in the group R1 include for example optionally substituted monocyclic or bicyclic fused ring C6-12 aromatic groups, such as phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups.
Optionally substituted heteroaromatic groups represented by the group Ar1 when present in the group R1 include for example optionally substituted C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five-or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example eight-to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups of these types include pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyi, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, [2,3-dihydro]benzothienyl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, e.g. 2,6-naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
Each aromatic or heteroaromatic group represented by the group Ar1 may be optionally substituted on any available carbon or, when present, nitrogen atom. One, two, three or more of the same or different substituents may be present and each substituent may be selected for example from an atom or group -L3(Alk2)tL4(R4)u in which L3 and L4, which may be the same or different, is each a covalent bond or a linker atom or group, t is zero or the integer 1, u is an integer 1, 2 or 3, Alk2 is an aliphatic or heteroaliphatic chain and R4 is a hydrogen or halogen atom or a group selected from optionally substituted C1-6alkyl, C3-8 cycloalkyl, C6-12aromatic or C1-9heteroaromatic, xe2x80x94OR5 [where R5 is a hydrogen atom, an optionally substitued C1-6alkyl or C3-8 cycloalkyl group], xe2x80x94SR5, xe2x80x94NR5R6 [where R6 is as just defined for R5 and may be the same or different], xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3H, xe2x80x94SOR5, xe2x80x94SO2R5, xe2x80x94SO3R5, xe2x80x94OCO2R5, xe2x80x94CONR5R6, xe2x80x94OCONR5R6, xe2x80x94CSNR5R6, xe2x80x94COR5, xe2x80x94OCOR5, xe2x80x94N(R5)COR6, xe2x80x94N(R5)CSR6, xe2x80x94SO2N(R5)(R6), xe2x80x94N(R5)SO2 R6, N(R5)CON(R6)(R7) [where R7 is a hydrogen atom, an optionally substituted C1-6alkyl or C3-8cycloalkyl group], xe2x80x94N(R5)CSN(R6)(R7) or xe2x80x94N(R5)SO2N(R6)(R7), provided that when t is zero and each of L3 and L4 is a covalent bond then u is the integer 1 and R4 is other than a hydrogen atom
Optionally substituted C6-12aromatic and C1-9heteroaromatic groups represented by R4 include those aromatic and heteroaromatic groups as described hereinbefore for the group Ar1. Optional substituents which may be present on these groups include those R13 optional substituents as described hereinafter.
When L3 and/or L4 is present in these substituents as a linker atom or group it may be any divalent linking atom or group. Particular examples include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R8)xe2x80x94 [where R8 is a hydrogen atom or an optionally substituted straight or branched C1-6alkyl group], xe2x80x94CON(R8)xe2x80x94, xe2x80x94OC(O)N(R8)xe2x80x94, xe2x80x94CSN(R8)xe2x80x94, xe2x80x94N(R8)COxe2x80x94, xe2x80x94N(R8)C(O)Oxe2x80x94, xe2x80x94N(R8)CSxe2x80x94, xe2x80x94S(O)2N(R8)xe2x80x94, xe2x80x94N(R8)S(O)2xe2x80x94, xe2x80x94N(R8)Oxe2x80x94, xe2x80x94ON(R8)xe2x80x94, xe2x80x94N(R8)N(R8)xe2x80x94, xe2x80x94N(R8)CON(R8)xe2x80x94, xe2x80x94N(R8)CSN(R8)xe2x80x94, or xe2x80x94N(R8)SO2N(R8)xe2x80x94 groups. Where the linker group contains two R8 substituents, these may be the same or different.
When R4, R5, R6, R7 and/or R8 is present as a C1-6alkyl group it may be a straight or branched C1-6 alkyl group, e.g. a C1-3alkyl group such as a methyl or ethyl group. C3-8cycloalkyl groups represented by R4, R5, R6, R7 and/or R8 include C3-6cycloalkyl groups e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Optional substituents which may be present on such groups include for example one, two or three substituents which may be the same or different selected from halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxy or C1-6alkoxy e.g. methoxy or ethoxy groups.
When the groups R5 and R6 or R6 and R7 are both C1-6alkyl groups these groups may be joined, together with the N atom to which they are attached, to form a heterocyclic ring. Such heterocyclic rings may be optionally interrupted by a further heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R5)xe2x80x94. Particular examples of such heterocyclic rings include piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings. When Alk2 is present as an aliphatic or heteroaliphatic chain it may be for example any divalent chain corresponding to the below-mentioned aliphatic or heteroaliphatic group described for Alk1 or R3 respectively.
Halogen atoms represented by R4 in the optional Ar1 substituents include fluorine, chlorine, bromine, or iodine atoms.
Examples of the substituents represented by -L3(Alk1)tL4(R4)u when present in Ar1 groups in compounds of the invention include atoms or groups -L3Alk2L4R4, -L3Alk2R4, -L3R4, xe2x80x94R4 and -Alk2R4 wherein L3, Alk2, L4 and R4 are as defined above. Particular examples of such substituents include -L3CH2L4R4, -L3CH(CH3)L4R4, -L3CH(CH2)2L4R4, -L3CH2R4, -L3CH(CH3)R4, -L3(CH2)2R4, xe2x80x94CH2R4, xe2x80x94CH(CH3)R4 , xe2x80x94(CH2)2R4 and xe2x80x94R4 groups.
Thus Ar1 in compounds of the invention may be optionally substituted for example by one, two, three or more halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, and/or C1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, C3-8cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C1-6hydroxyalkyl, e.g. hydroxymethyl, hydroxyethyl or xe2x80x94C(OH)(CF3)2, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxy-propylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, haloC1-6alkyl, e.g. xe2x80x94CF3, xe2x80x94CHF2, CH2F, haloC1-6alkoxy, e.g. xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2F, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylamino-ethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylamino-propoxy, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk3 [where Alk3 is as defined below for Alk7], C1-6 alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, sulphonyl (xe2x80x94SO3H), xe2x80x94SO3Alk3, C1-6alkylsulphinyl, e.g. methylsulphinyl, C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylamino-sulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkyl-aminocarbonyl aminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylamino-carbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e.g. diethylam inoethylam inocarbonyl, aminocarbonylamino, C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylamino C1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino groups.
L2 when present as part of the group R1 in compounds of the invention may be a linker atom or group L2a or a linker -(Alka)L2a-, where Alka is an optionally substituted aliphatic or heteroaliphatic chain as previously defined for Alk2, and L2a is a linker atom or group as described above for L3 and L4.
Optionally substituted arylene groups represented by Ar2 when present as part of the group R1 include those aromatic groups as previously described for Ar1.
Optionally substituted heteroarylene groups represented by Ar2 when present as part of the group R1 include those heteroaromatic groups as previously described for Ar1.
Each arylene or heteroarylene group represented by Ar2 may be attached to the remainder of the molecule through any available ring carbon or nitrogen atoms.
The arylene and heteroarylene groups represented by Ar2 may be optionally substituted by one, two or more substituents selected from the atoms or groups -L3(Alk2)tL4(R4)u described herein. Where two of these atoms or groups are present they may be the same or different.
When the group R is present in R1 in compounds of the invention as a derivative of a carboxylic acid it may be for example a carboxylic acid ester or amide. Particular esters and amides include xe2x80x94CO2Alk7 and xe2x80x94CONR5R6 groups as defined herein. When R is a biostere of a carboxylic acid it may be for example a tetrazole or other acid such as phosphonic acid, phosphinic acid, sulphonic acid, sulphinic acid or boronic acid or an acylsulphonamide group.
Esters (xe2x80x94CO2Alk7) and amide (xe2x80x94CONR5R6) derivatives of the carboxylic acid group (xe2x80x94CO2H) in compounds of formula (1) may advantageously be used as prodrugs of the active compound. Such prodrugs are compounds which undergo biotransformation to the corresponding carboxylic acid prior to exhibiting their pharmacological effects and the invention particularly extends to produgs of the acids of formula (1). Such prodrugs are well known in the art, see for example International Patent Application No. WO00123419, Bodor, N. (Alfred Benzon Symposium, 1982, 17, 156-177), Singh, G. et al (J. Sci. Ind. Res., 1996, 55, 497-510) and Bundgaard, H., (Design of Prodrugs, 1985, Elsevier, Amsterdam).
Esterified carboxyl groups represented by the group xe2x80x94CO2Alk7 wherein Alk7 include groups is a straight or branched optionally substituted C1-8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group, an optionally substituted C2-8alkenyl group such as a propenyl e.g. 2-propenyl or butenyl e.g. 2-butenyl or 3-butenyl group, an optionally substituted C2-8alkynyl group such as a ethynyl, propynyl e.g. 2-propynyl or butynyl e.g. 2-butynyl or 3-butynyl group, an optionally substituted C3-8cycloalkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group; an optionally substituted C3-8cycloalkyl C1-8alkyl group such as a cyclopentylmethyl, cyclohexylmethyl or cyclohexylethyl group; an optionally substituted C3-8heterocycloalkylC1-6alkyl group such as a morpholinyl-N-ethyl, thiomorpholinyl-N-methyl, pyrrolidinyl-N-ethyl, pyrrolidinyl-N-propyl, piperidinyl-N-ethyl, pyrazolidinyl-N-methyl or piperazinyl-N-ethyl group; an optionally substituted C1-6alkyloxy C1-6alkyl group such as a methyloxyethyl or propyloxyethyl group; an optionally substituted C1-6alkylthioC1-6alkyl group such as an ethylthioethyl group; an optionally substituted C1-6alkylsufinylC1-6alkyl group such as an methylsulfinylethyl group; an optionally substituted C1-6alkylsulfonylC1-6alkyl group such as an methylsulfonylmethyl group; an optionally substituted C3-8cycloalkyloxyC1-6alkyl group such as a cyclohexyloxy-methyl group; an optionally substituted C3-8cycloalkylthioC1-6alkyl group such as a cyclopentylthiomethyl group; an optionally substituted C3-8cycloalkylsulfinylC1-6alkyl group such as a cyclopentylsulfinylmethyl group; an optionally substituted C3-8cycloalkylsulfonylC1-6alkyl group such as a cyclopentylsulfonylmethyl group; an optionally substituted C1-6alkyloxycarbonylC1-6alkyl group such as isobutoxycarbonylpropyl group; an optionally substituted C1-6alkyloxycarbonylC1-6alkenyl group such as isobutoxycarbonylpentenyl group; an optionally substituted C1-6alkyloxycarbonyloxyC1-6alkyl group such as an isopropoxycarbonyloxyethyl e.g a 1-(isopropoxycarbonyloxy) ethyl, 2-(isopropoxycarbonyloxy)ethyl or ethyloxycarbonyloxymethyl group; an optionally substituted C1-6alkyloxycarbonyloxyC1-6alkenyl group such as a isopropoxycarbonyloxybutenyl group, an optionally substituted C3-8cycloalkyloxycarbonyloxyC1-6alkyl group such as a cyclohexyloxycarbonyloxyethyl, e.g. a 2-(cyclohexyloxycarbonyloxy)ethyl group, an optionally substituted N-di-C1-8alkylaminoC1-8alkyl group such as a N-dimethylaminoethyl or N-diethylaminoethyl group; an optionally substituted Nxe2x80x94C6-12aryl-Nxe2x80x94C1-6alkylaminoC1-6alkyl group such as a N-phenyl-N-methylaminomethyl group; an optionally substituted N-di-C1-8alkylcarbamoyl C1-8alkyl group such as a N-diethylcarbamoylmethyl group; an optionally substituted C6-10arylC1-6alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-10aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-10aryloxyC1-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; a C6-12arylthioC1-8alkyl group such as an optionally substituted phenylthioethyl group; a C6-12arylsulfinylC1-8alkyl group such as an optionally substituted phenylsulfinylmethyl group; a C6-12arylsulfonylC1-8alkyl group such as an optionally substituted phenylsulfonylmethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a acetoxymethyl, ethoxycarbonyloxyethyl, pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; an optionally substituted C4-8imidoC1-8alkyl group such as a succinimidomethyl or phthalamidoethyl group; a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group or a triglyceride such as a 2-substituted triglyceride e.g. a 1,3-di-C1-8alkylglycerol-2-yl group such as a 1,3-diheptylglycerol-2-yl group. Optional substituents present on the Alk7 group include R13asubstituents described above.
Optional substituents which may be present on the Alk7 group include R13a substituents as defined hereinafter.
When the group R2 is present in compounds of the invention as a C1-6alkyl group it may be for example a straight or branched C1-6alkyl group, e.g. a C1-3alkyl group such as a methyl or ethyl group.
Unsaturated cycloaliphatic groups represented by the ring Cy include unsaturated C4-10 cycloaliphatic groups. Particular examples of unsaturated cycloaliphatic groups represented by Cy include C3-7cycloalkenyl groups.
Particular examples of unsaturated cycloaliphatic groups represented by Cy include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl groups.
Unsaturated heterocycloaliphatic groups represented by the ring Cy include unsaturated C3-10heterocycloaliphatic groups. Particular examples include optionally substituted C3-10 heterocycloalkenyl e.g. C3-7 heterocycloalkenyl groups, each of said groups containing one, two, three or four heteroatoms or heteroatom containing groups L7 where L7 is as defined above for L3 where L3 is a linker atom or group. It will be appreciated that when X in the ring Cy is a nitrogen atom then a further heteroatom or heteroatom containing group L7 need not be present in the ring Cy.
Particular examples of unsaturated heterocycloaliphatic groups represented by Cy include dihydrofuranyl, dihydrothiophenyl, 2,3-dihydrothiophene-1,1-dioxide, 3-amino4,5-dihydro-1,1-dioxothiophenyl [where amino refers to the group NR1 R2], 3,4-dihydrol-1,1 -dioxo-2H-thiopyranyl, 2,3,4,5-tetrahydro-1,1-dioxo-thiopinyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, oxazolinyl, thia-zolinyl, imidazolinyl, pyrazolinyl, isoxazolinyl, isothiazolinyl, pyranyl, dihydropyridyl, tetrahydropyridyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrahydro-pyrazinyl, dihydrotriazinyl, tetrahydrotriazinyl, oxazinyl or dihydrothiadia-zinyl group.
When the unsaturated cycloaliphatic or heterocycloaliphatic ring represented by Cy is substituted by a group Rx, Rx may be a oxo (xe2x95x90O), thioxo (xe2x95x90S) or imino (xe2x95x90NR30) group. It will be understood that when the ring Cy includes such a group Rx, then the corresponding hydroxy (xe2x80x94OH), thiol (xe2x80x94SH) or amino (xe2x80x94NHR30) tautomers in which the double bond migrates to become part of the ring Cy are also included.
When the group R30 is present in compounds of formula (1) as an aliphatic group it may be any aliphatic chain as described hereinafter for Alk1 but with each containing a terminal hydrogen atom. When the group R30 is present in compounds of formula (1) as a heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group it may be any heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group as described hereinafter for the group R3. Optional substituents which may be present on these groups include any optional substituents described herein in relation to the corresponding Alk1 aliphatic chains or R3 heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic groups.
The group Rz when present may be attached to any suitable carbon or nitrogen atom of the unsaturated cycloaliphatic or heterocycloaliphatic ring represented by Cy.
Halogen atoms represented by the group Rz include fluorine, chlorine, bromine and iodine atoms.
C1-3alkylene chains represented by Alk4 in the group Rz in compounds of formula (1) include for example a xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94 or xe2x80x94CH2CH(CH3)xe2x80x94 chain.
When present the linker atom or group represented by L1 in the group Rz in compounds of formula (1) may be any linker atom or group as described above for the linker atom or group L3.
When Alk1 is present in the group Rz in compounds of formula (1) as an optionally substituted aliphatic chain it may be an optionally substituted C1-10 aliphatic chain. Particular examples include optionally substituted straight or branched chain C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene chains.
Particular examples of aliphatic chains represented by Alk1 include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94(CH2 )2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, xe2x80x94(CH2 )2CH2xe2x80x94, xe2x80x94(CH2)3CH2xe2x80x94, xe2x80x94CH(CH3)(CH2)2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CH2xe2x80x94, xe2x80x94CH2C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)2C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)4CH2xe2x80x94, xe2x80x94(CH2)5CH2xe2x80x94, xe2x80x94CHCHxe2x80x94, xe2x80x94CHCHCH2xe2x80x94, xe2x80x94CH2CHCHxe2x80x94, xe2x80x94CHCHCH2CH2xe2x80x94, xe2x80x94CH2CHCHCH2xe2x80x94, xe2x80x94(CH2)2CHCHxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94CCCH2xe2x80x94, xe2x80x94CH2CCxe2x80x94, xe2x80x94CCCH2CH2xe2x80x94, xe2x80x94CH2CCCH2xe2x80x94 or xe2x80x94(CH2)2CCHxe2x80x94 groups.
Heteroaliphatic groups represented by the group R3 when present in the group Rz in compounds of formula (1) include the aliphatic chains just described for Alk1 but with each containing a terminal hydrogen atom and additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L5 where L5 is as defined above for L3 when L3 is a linker atom or group. Each L5 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group. Particular examples include optionally substituted -L5CH3, xe2x80x94CH2L5CH3, -L5CH2CH3, xe2x80x94CH2L5CH2CH3, xe2x80x94(CH2)2L5CH3, xe2x80x94(CH2)3L5CH3, -L5(CH2)3, and xe2x80x94(CH2)2L5CH2CH3 groups.
The optional substituents which may be present on aliphatic chains or heteroaliphatic groups represented by Alk1 and R3 respectively or aliphatic groups represented by -Alk1 R3 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or xe2x80x94OH, xe2x80x94CO2H, xe2x80x94CO2R9, where R9 is an optionally substituted straight or branched C1-6alkyl group as defined above for R4, xe2x80x94CONHR9, xe2x80x94CON(R9)2, xe2x80x94COR9, xe2x80x94COCH3, C1-6alkoxy, e.g. methoxy or ethoxy, haloC1-6alkoxy e.g. xe2x80x94OCF3, thiol, xe2x80x94S(O)R9, xe2x80x94S(O)2R9, C1-6alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include xe2x80x94NHR9 and xe2x80x94N(R9)2 groups. Where two R9 groups are present in any of the above substituents these may be the same or different.
Optionally substituted cycloaliphatic groups represented by the group R3 when present in the group Rz in compounds of the invention include optionally substituted C3-10 cycloaliphatic groups. Particular examples include optionally substituted C3-10 cycloalkyl, e.g. C3-7 cycloalkyl or C3-10 cycloalkenyl, e.g C3-7 cycloalkenyl groups.
Optionally substituted heterocycloaliphatic groups represented by the group R3 when present in the group Rz include optionally substituted C3-10heterocycloaliphatic groups. Particular examples include optionally substituted C3-10heterocycloalkyl, e.g. C3-7 heterocycloalkyl, or C3-10heterocycloalkenyl, e.g. C3-7 hetercycloalkenyl groups, each of said groups containing one, two, three or four heteroatoms or heteroatom-containing groups L5 as defined above.
Optionally substituted polycycloaliphatic groups represented by the group R3 when present in the group Rz include optionally substitued C7-10 bi-or tricycloalkyl or C7-10-bi-or tricycloalkenyl groups. Optionally substituted heteropolycycloaliphatic groups represented by the group R3 include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L5 atoms or groups.
Particular examples of cycloaliphatic, polycycloaliphatic, heterocycloaliphatic and heteropolycycloaliphatic groups represented by the group R3 include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1 -yl, 3-cyclo-penten-1-yl, adamantyl, norbornyl, norbornenyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrroline, e.g. 2-or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, piperidinone, 1,4-dioxanyl, morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-,6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, e.g. o-or p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5,-oxadiazinyl groups.
The optional substituents which may be present on the cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or heteropolycycloaliphatic groups represented by the group R3 include one, two, three or more substituents each selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl, ethyl or propyl, haloC1-6alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g. xe2x80x94C(OH)(CF3)2, C1-6alkoxy, e.g. methoxy, ethoxy or propoxy, haloC1-6-alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, C1-6alkylthio e.g. methylthio, ethylthio or propylthio, or -(Alk4a)gR10 groups in which Alk4a is a straight or branched C1-3alkylene chain, g is zero or an integer 1 and R10 is a xe2x80x94OH, xe2x80x94SH, xe2x80x94N(R11)2, (in which R11 is an atom or group as defined herein for R8) xe2x80x94CN, xe2x80x94CO2R11, xe2x80x94NO2, xe2x80x94CON(R11)2, xe2x80x94CSN(R11)2, xe2x80x94COR11, xe2x80x94CSN(R11)2, xe2x80x94N(R11)COR11, xe2x80x94N(R11)CSR11, xe2x80x94SO2N(R11)2, xe2x80x94N(R11)SO2R11, xe2x80x94N(R11)CON(R11)2, xe2x80x94N(R11)CSN(R11), N(R11)SO2N(R11)2 or optionally substituted phenyl group. Where two R11 atoms or groups are present in these substituents these may be the same or different. Optionally substituted phenyl groups include phenyl substituted by one, two or three of the R13 groups described below
Additionally, when the group R3 is a heterocycloaliphatic group containing one or more nitrogen atoms each nitrogen atom may be optionally substituted by a group -(L6)p(Alk5)qR12 in which L6 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CON(R11)xe2x80x94, xe2x80x94CSN(R11)xe2x80x94 or SO2N(R11)xe2x80x94; p is zero or an integer 1; Alk5 is an optionally substituted aliphatic or heteroaliphatic chain; q is zero or an integer 1; and R12 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycyclo-aliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group.
C1-3alkylene chains represented by Alk4a include those groups as previously described for Alk4.
Optionally substituted aliphatic or heteroaliphatic chains represented by Alk5 include those optionally substituted chains described above for Alk1 and R3 respectively. Optional substituents which may be present on these groups include those described above in relation to Alk1 and R3 aliphatic and heteroaliphatic chains.
Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic or polyheterocycloaliphatic groups represented by R12 include those groups just described for the group R3. Optional substituents which may be present on those groups include those described above in relation to R3 cycloaliphatic groups.
Aromatic or heteroaromatic groups represented by R12 include those groups described herein for the group Ar1. Optional substituents which may be present on these groups include those R13 optional substituents described hereinafter.
When the group R3 is an optionally substituted aromatic or heteroaromatic group it may be for example an aromatic or heteroaromatic group as described herein for the group Ar1.
Optional substituents which may be present on the aromatic or heteroaromatic groups represented by the group R3 include one, two, three or more substituents, each selected from an atom or group R13 in which R13 is xe2x80x94R13a or -Alk6(R13a)m, where R13a is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR14 [where R14 is an -Alk6(R13a)m, aryl or heteroaryl group], xe2x80x94CSR14, xe2x80x94SO3H, xe2x80x94SOR14, xe2x80x94SO2R14, xe2x80x94SO3R14, xe2x80x94SO2NH2, xe2x80x94SO2NHR14 SO2N(R14)2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR14, xe2x80x94CSNHR14, xe2x80x94CON[R14]2, xe2x80x94C S N (R14)2, xe2x80x94N (R11)SO2R14, xe2x80x94N(SO2R14)2,l xe2x80x94NH(R11)SO2NH2, xe2x80x94N(R11)SO2NHR14, xe2x80x94N(R11)SO2N(R14)2, xe2x80x94N(R11)COR14, xe2x80x94N(R11)CONH2, xe2x80x94N(R11)CONHR14, xe2x80x94N(R11)CON(R14)2, xe2x80x94N(R11)CSNH2, xe2x80x94N(R11)CSNHR14, xe2x80x94N(R11)CSN(R14)2, xe2x80x94N(R11)CSR14, xe2x80x94N(R11)C(O)OR14, xe2x80x94SO2NHet1 [where -NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, S(O) or xe2x80x94S(O)2 groups], -CONHet1, -CSNHet1, xe2x80x94N(R11)SO2NHet1, xe2x80x94N(R11)CONHet1, xe2x80x94N(R11)CSNHet1, xe2x80x94SO2N(R11)Het2 [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], -Het2, xe2x80x94CON(R11)Het2, xe2x80x94CSN(R11)Het2, xe2x80x94N(R11)CON(R11)Het2, xe2x80x94N( R11)CSN(R11)Het2, cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group; Alk6 is a straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94S(O)n [where n is an integer 1 or 2] or xe2x80x94N(R15)xe2x80x94 groups [where R15 is a hydrogen atom or C1-6alkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1, 2 or 3. It will be appreciated that when two R11 or R14 groups are present in one of the above substituents, the R11 or R14 groups may be the same or different.
When in the group -Alk6(R13a)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R13a may be present on any suitable carbon atom in -Alk6. Where more than one R13a substituent is present these may be the same or different and may be present on the same or different atom in -Alk6. Clearly, when m is zero and no substituent R13a is present the alkylene, alkenylene or alkynylene chain represented by Alk6 becomes an alkyl, alkenyl or alkynyl group.
When R13a is a substituted amino group it may be for example a group xe2x80x94NHR14 [where R14 is as defined above] or a group xe2x80x94N(R14)2 wherein each R14 group is the same or different.
When R13a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R13a is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR14 or a xe2x80x94SR14 or xe2x80x94SC(xe2x95x90NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R13a include groups of formula xe2x80x94CO2Alk7 wherein Alk7 is a group as defined hereinbefore.
When Alk6 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R9)xe2x80x94 groups.
Cycloaliphatic or heterocycloaliphatic groups represented by the groups R13a or R14 include those optionally substituted C3-10cycloaliphatic or C3-10heterocycloaliphatic groups described above for R3.
Aryl or heteroaryl groups represented by the groups R13a or R14 include mono-or bicyclic optionally substituted C6-12 aromatic or C1-9 heteroaromatic groups as described above for the group Ar1. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
When -NHet1 or -Het2 forms part of a substituent R13 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or -Het2 include those R7 substituents described above.
Particularly useful atoms or groups represented by R13 include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, e.g. t-butyloxycarbonylpiperazinyl, pyrrolidinyl, dioxolanyl, dioxanyl, oxazolidinyl, thiazolidinyl, imidazolidinyl or piperidinyl, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C4-7cycloalkyl, e.g. cyclobutyl, cyclopentyl, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC1-6alkyl, e.g. trifluoromethyl, haloC1-6alkoxy, e.g. trifluoromethoxy, C1-6alkylamino, e.g. methylamino, ethylamino or propylamino, C6-12arylC1-6alkylamino, e.g. benzylamino, 4-fluorobenzyl-amino or 4-hydroxyphenylethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, aminoC1-6alkylamino, e.g. aminoethylamino or aminopropylamino, optionally substituted Het1NC1-6alkylamino, e.g. 3-morpholinopropylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, hydroxyC1-6alkylamino, e.g. 2-hydroxyethylamino, 3-hydroxypropylamino or 3-hydroxybutylamino, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk7 [where Alk7 is as defined above], C1-6alkanoyl e.g. acetyl, propyryl or butyryl, optionally substituted benzoyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(xe2x95x90NH)NH2, sulphonyl (xe2x80x94SO3H), xe2x80x94SO3Alk7, C1-6alkylsulphinyl, e.g. methylsulphinyl, ethylsuiphinyl or propylsulphinyl, C1-6alkylsulphonyl, e.g. methylsulphonyl, ethylsulphonyl or propylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl, ethylaminosulphonyl or propylaminosulphonyl C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6alkylaminoC1-6alkylaminocarbonyl, e.g. methylaminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkyl-aminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonyl-amino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, xe2x80x94CONHC(xe2x95x90NH)NH2, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, haloC1-6alkylsulphonylamino, e.g. trifluoromethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC1-6alkylamino, optionally substituted phenylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, benzyloxycarbonylaminoC1-6alkyl e.g. benzyloxycarbonylaminoethyl, thiobenzyl, pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two R13 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R13 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group represented by R3.
Where desired two Rz substituents attached to a single carbon atom of the ring Cy may be linked together to form an optionally substituted spiro-linked monocyclic C3-7cycloaliphatic or C2-7heterocycloaliphatic group. C3-7cycloaliphatic groups of this type include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl and cyclohexenyl groups. C2-7heterocycloaliphatic groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and tetrahydrothiophenyl groups. Optional substituents which may be present on such groups include those optional substituents described hereinbefore in relation to R3 cycloaliphatic and heterocycloaliphatic groups.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
In the compounds according to the invention the group R1 is preferably an Ar1L2Ar2Alk- group. In compounds of this type Ar1 is preferably an optionally substituted phenyl, monocyclic heteroaromatic or bicyclic heteroaromatic group. Particularly useful monocyclic heteroaromatic groups are optionally substituted five-or six-membered heteroaromatic groups as described previously, especially five-or six-membered heteroaromatic groups containing one or two heteroatoms selected from oxygen, sulphur or nitrogen atoms. Nitrogen-containing groups are especially useful, particularly pyridyl or pyrimidinyl groups. Particularly useful substituents present on these Ar1 groups include halogen atoms or alkyl, haloalkyl, xe2x80x94OR5, xe2x80x94SR5, xe2x80x94NR5R6, xe2x80x94CO2H, xe2x80x94CO2CH3, xe2x80x94NO2, xe2x80x94N(R5)COR6 or xe2x80x94CN groups as described above in relation to the compounds of formula (1). Particularly useful bicyclic heteroaromatic groups represented by Ar1 include optionally substituted ten-membered fused-ring heteroaromatic groups containing one or two heteroatoms, especially nitrogen atoms. Particular examples include optionally substituted naphthyridinyl, especially 2,6-naphthyridinyl and 2,7-naphthyridinyl, quinolinyl and isoquinolinyl, especially isoquinolin-1-yl groups. Particular optional substituents include those just described for monocyclic heteroaromatic groups. In compounds according to the invention the ring Cy is preferably an optionally substituted unsaturated cycloaliphatic or heterocycloaliphatic ring. One particularly useful class of Cy rings is that in which m is the integer 1 and Rx represents an oxo substituent (xe2x95x90O) on a carbon atom adjoined to the group X. A further particularly useful class of Cy rings is that in which m is zero, X is a C(Rw) group and the ring Cy contains an L7 sulfoxide or sulfone heteroatom containing group within its ring structure.
A particularly useful group of compounds according to the invention has the formula (2a): 
wherein xe2x80x94Wxe2x95x90is xe2x80x94CHxe2x95x90 or xe2x80x94Nxe2x95x90;
R16 and R17, which may be the same or different is each a hydrogen atom or an atom or group -L3(Alk2)tL4(R4)u in which L3, Alk2, t, L4R4 and u are as defined previously;
L2, Ar2, Alk, R2, Cy, X, Rz and p are as defined for formula (1);
provided that Cy is other than a cyclobutenedione group;
and the salts, solvates, hydrates and N-oxides thereof.
In one particularly useful class of compounds of formula (2a) xe2x80x94Wxe2x95x90 is a xe2x80x94Nxe2x95x90atom.
In anoher particularly useful class of compounds of formula (2a) xe2x80x94Wxe2x95x90 is a xe2x80x94CHxe2x95x90group.
R16 and R17 in compounds of formula (2a) is each preferably as particularly described above for compounds of formula (1), other than a hydrogen atom. Particularly useful R16 and R17 substituents include halogen atoms, especially fluorine or chlorine atoms, or methyl, halomethyl, especially xe2x80x94CF3, xe2x80x94CHF2 or xe2x80x94CH2F, methoxy or halomethoxy, especially xe2x80x94OCF3, xe2x80x94OCHF2 or xe2x80x94OCH2F groups.
A further particularly useful group of compounds according to the invention has the formula (2b): 
wherein R16, L2, Ar2, Alk, Cy, R2, X, Rz and p are as defined for formula (2a);
g is the integer 1, 2, 3 or 4.
provided that Cy is other than a cyclobutenedione group;
and the salts, solvates, hydrates and N-oxides thereof.
Each R16 atom or group in compounds of formula (2b) may be independently selected from an atom or group -L3(Alk2)tL4(R4)u in which L2, Alk2, t, L3, R4 and u are as previously defined. Particularly useful R16 substituents when present in compounds of formula (2b) include halogen atoms, especially fluorine or chlorine atoms, or straight or branched C1-6alkyl, especially methyl, ethyl or isopropyl, C3-8cycloalkyl especially cyclopropyl, haloC1-6alkyl, especially halomethyl, most especially xe2x80x94CF3 or xe2x80x94CHF2, straight of branched C1-6alkoxy, especially methoxy or ethoxy, haloC1-6alkoxy, especially halomethoxy, most especially xe2x80x94OCF3 or xe2x80x94OCHF2, xe2x80x94SR5 especially methylthio or ethylthio, xe2x80x94CN, xe2x80x94CO2Alk3, especially xe2x80x94CO2CH3, xe2x80x94NO2, amino (xe2x80x94NH2), substituted amino (xe2x80x94NR5R6), xe2x80x94N(R5)COR6, especially xe2x80x94NHCOCH3, xe2x80x94COR5, especially xe2x80x94COCH3, optionally substituted C6-12aromatic, especially optionally substituted phenyl and C1-9heteroaromatic groups, especially optionally substituted thienyl, pyridyl and pyrimidinyl groups.
A further particularly useful group of compounds according to the invention has the formula (2c): 
wherein R16, g, L2, Ar2, Alk, Cy, R2, X, Rz and p are as defined for formula (2b);
provided that Cy is other than a cyclobutenedione group;
and the salts, solvates, hydrates and N-oxides thereof.
Each R16 atom or group in compounds of formula (2d) may be independently selected from an atom or group -L3(Alk2)tL4(R4)u as previously defined for compounds of formula (2b).
In one particularly preferred class of compounds of formula (2c) g is zero.
In another particularly preferred class of compounds of formula (2c) g is the integer 1 or 2.
An especially preferred class of compounds of formula (2c) is that where g is the integer 1 and R16 is a substituent at the 3-position of the 2,7-naphthyridine ring. In this class of compounds R16 is most preferably a methyl or halomethyl, especially xe2x80x94CF3 group, or an optionally substituted phenyl group.
Particularly useful optional substituents which may be present on R16 aromatic and heteroaromatic groups when present in compounds of formula (2b) or (2c) include halogen atoms, especially fluorine and chlorine atoms, C1-6alkyl groups, especially fluorine and chlorine atoms, C1-6alkyl groups, especially methyl, ethyl and i-propyl groups and xe2x80x94CF3, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94OCH(CH3)2, xe2x80x94OCF3, xe2x80x94SCH3, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94CN, xe2x80x94CO2CH3, xe2x80x94COCH3, and xe2x80x94N(CH3)COCH3 groups.
A further particularly useful group of compounds according to the invention has the formula (2d): 
wherein R16, g, L2, Ar2, Alk, Cy, R2, X, Rz and p are as defined for formula (2b);
provided that Cy is other than a cyclobutenedione group;
and the salts, solvates, hydrates and N-oxides thereof.
Each R16 atom or group in compounds of formula (2d) may be independently selected from an atom or group -L3(Alk2)tL4(R4)u as previously defined for compounds of formula (2b).
In one preferred class of compounds of formula (2d) g is zero.
In another preferred class of compounds of formula (2d) g is the integer 1. In this class of compounds R16 is preferably a substituent at the 3-positions of the isoquinoline ring as just defined. Most especially useful R16 substituents of this type include halogen atoms, especially fluorine and chlorine atoms and straight or branched C1-6alkyl groups, especially methyl, ethyl or isopropyl, most especially methyl groups.
In another preferred class of compounds of formula (2d) g is the integer 2 or 3 where one R16 group is as just generally and particularly defined, and is located at the 3-position of the isoquinoline ring. In this class of compounds the second and when present third R16 optional substituents may be selected from an R16 optional substituent as described for compounds of formula (2b) or when g is the integer 3 a C1-6alkylenedioxy group, especially a methylenedioxy or ethylenedioxy group. In one particularly useful group of compounds of this class g is the integer 2 where one R16 group is at the 3-position of the isoquinoline ring as previously generally and particularly described and the other R16 group is at the 6-, 7-or 8-position of the isoquinoline ring, most especially the 7-position. Most especially preferred substituents at the 7-position include a halogen atom, especially a fluorine or chlorine atom, or a C1-6alkoxy group, especially a methoxy group.
It will be understood that compounds according to formulae (2a), (2b), (2c) and (2d) include, where applicable, the corresponding hydroxy tautomers.
Alk in compounds of the invention is preferably: 
or, especially, xe2x80x94CH2CH(R)xe2x80x94.
In one preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) R2 is a hydrogen atom.
In another preferred class of the compounds of formulae (1), (2a), (2b), (2c) and (2d) R is preferably a xe2x80x94CO2H group.
In a further preferred class of compounds of formulae (1) and (2) R is an esterified carboxyl group of formula xe2x80x94CO2Alk7. In this class of compound Alk7 is preferably a C1-8alkyl group, especially a methyl, ethyl, propyl or i-propyl group, an optionally substituted C6-10aryl group, especially a phenyl group, an optionally substituted C6-10arylC1-6alkyl group, especially a benzyl group, a C3-8heterocycloalkylC1-6alkyl group, especially a morpholinyl-N-ethyl group or a C1-6alkyloxyC1-6alkyl group, especially a methyloxyethyl group. Especially preferred esterified carboxyl groups include xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3, xe2x80x94CO2 CH2CH2CH3 and xe2x80x94CO2CH(CH3)2 groups.
In general in compounds of formula (2a) when W is a xe2x80x94Nxe2x95x90 atom, L2 is preferably L2a where L2a is a xe2x80x94CON(R8)xe2x80x94group, especially xe2x80x94CONHxe2x80x94 or -(Alka)L2a- where -(Alka)L2a- is especially a xe2x80x94CH2Oxe2x80x94 group. Most preferred is a xe2x80x94CONHxe2x80x94 group.
In general in compounds of formula (2a) when W is a xe2x80x94CHxe2x95x90group L2 is preferably a covalent bond or L2a where L2a is a xe2x80x94CON(R)8xe2x80x94 group, especially xe2x80x94CONHxe2x80x94 or -(Alka)L2a- where -(Alka)L2a- is especially a xe2x80x94CH2Oxe2x80x94group. When W in compounds of formula (2a) is a xe2x80x94CHxe2x95x90group L2 is most preferably a covalent bond.
In general in compounds of formula (2b), (2c) and (2d) L2 is preferably L2a where L2a is an xe2x80x94Oxe2x80x94 atom or xe2x80x94N(R8)xe2x80x94 group. An especially useful xe2x80x94N(R8)xe2x80x94 group is xe2x80x94NHxe2x80x94.
The group Ar2 in compounds of formulae (1), (2a), (2b), (2c) and (2d) is preferably an optionally substituted phenylene group. Particularly useful groups include optionally substituted 1,4-phenylene groups.
The ring Cy in compounds of formulae (1), (2a), (2b), (2c) and (2d) is preferably an optionally substituted cyclopentenyl, cyclohexenyl, cyclohepenyl, dihydropyrimidinyl, dihydropyridinyl or imidazolinyl group, each containing a oxo substituent (xe2x95x90O) within their ring structure on the carbon atom adjoined to the group X.
It will be understood that the corresponding hydroxy (xe2x80x94OH) tautomers of those oxo (xe2x95x90O) containing Cy rings, where the double bond migrates to become part of the Cy ring structure are also included in the definition or preferred Cy rings.
In one preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) the group X in the unsaturated heteroaliphatic ring represented by Cy is preferably a N atom. Preferred Cy rings containing this X group include optionally substituted 2-aminopyrimidin-4-ones [where amino refers to the group xe2x80x94N(R2)-], 4-aminopyrim idin-2-ones, 2-aminopyridin-4-ones, 6-amino-pyridin-2-ones and 2-aminoimidazolin-4-ones.
In another preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) the group X in the unsaturated cycloaliphatic or heteroaliphatic ring represented by Cy is preferably a C(Rw) group. Particularly useful Rw atoms and groups that may be present in the group X include hydrogen and halogen atoms, especially fluorine, chlorine or bromine atoms or nitro, C1-6alkyl, especially xe2x80x94CH3, xe2x80x94CH2 CH3, xe2x80x94CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CH(CH3)2, xe2x80x94C(CH3)3, xe2x80x94CH(CH2CH3)2, xe2x80x94CH2CH(CH3)2, and xe2x80x94CH2C(CH3)3 C2-6alkynylene, especially xe2x80x94CH2CHCH2 and xe2x80x94CH2CH2CHCH2, C2-6alkylnylene especially xe2x80x94CH2CCH and xe2x80x94CH2CH2CCH, optionally substituted C1-6alkylC6-12aromatic, especially optionally substituted benzyl or phenylethyl, optionally substituted C6-12aromatic, especially optionally substituted phenyl, optionally substituted C3-10ocycloaliphatic, especially optionally substituted C3-7cycloalkyl, most especially optionally substituted cyclopentyl, cyclohexyl or cycloheptyl or optionally substituted C3-10heterocycloaliphatic especially C3-7heterocycloalkyl, most especially tetrahydropyranyl and tetrahydrothiopyranyl groups. Particularly preferred Cy rings in compounds of formulae (1), (2a), (2b), (2c) and (2d) containing such X groups include optionally substituted 3-amino-2-cyclopenten-1 -one [where amino refers to the group xe2x80x94N(R2)xe2x80x94] and 3-amino-2-cyclohexen-1-one rings.
In general in compounds of formula (1), (2a), (2b), (2c) and (2d) p is preferably zero or the integer 1 or 2.
In one preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) p is zero or the integer 1 or 2. In this class of compounds Cy is preferably an optionally substituted 3-amino-2-cyclopenten-1-one ring. In one most preferred group of compounds of this class p is zero.
In another preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) p is zero or the integer 1 or 2. In this class of compounds Cy is preferably an optionally substituted 3-amino-2-cyclohexen-1 one ring.
In general in compounds of formulae (1), (2a), (2b), (2c) and (2d) when v and n in the group Rz are zero or the integer 1 the group R3 may especially be an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group as defined herein. Particularly useful groups of this type include optionally substituted C2-6heteroalkyl, particularly C1-3alkoxyC1-3alkyl, especially methoxypropyl, optionally substituted C3-7cycloalkyl, especially optionally substituted cyclopropyl, cyclobutyl cyclopropyl or cyclohexyl, optionally substituted C5-7heterocycloaliphatic, optionally substituted pyrrolidinyl or thiazolidinyl, optionally substituted phenyl and optionally substituted C5-7heteroaromatic, especially optionally substituted pyridyl groups. Optional substituents on these groups include in particular R13 atoms or groups where the group is an aromatic or heteroaromatic group and -(L6)p(Alk5)qR12 groups as described earlier where the group is a nitrogen-containing heterocycloaliphatic group such as a pyrrolidinyl or thiazolidinyl group. Particularly useful -(L6)p(Alk5)qR12 groups include those in which L6 is a xe2x80x94COxe2x80x94 group. Alk5 in these groups is preferably present (i.e. q is preferably an integer 1) and in particular is a xe2x80x94CH2xe2x80x94 chain. Compounds of this type in which R12 is a hydrogen atom or an optionally substituted aromatic or heteroaromatic group, especially an optionally substituted phenyl, pyridyl or imidazolyl group are particularly preferred.
In another preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) v is zero, Alk1 in the group Rz is present as an optionally substituted aliphatic chain as defined herein (i.e. n is the integer 1) and R3 is a hydrogen atom. Compounds of this type where -Alk1R3 is an optionally substituted C1-6 alkyl group, particularly a methyl, ethyl, n-propyl i-propyl, i-butyl, t-butyl or n-butyl group or an allyl (xe2x80x94CH2CHCH2) or (propargyl) xe2x80x94CH2CCH group are especially useful. In one preferred group of compounds of this type L1 is a covalent bond. In another preferred group of compounds of this type L1 is a group xe2x80x94N(R8)xe2x80x94 as previously generally and particularly defined.
Particularly preferred optional substituents which may be present on aliphatic groups of formula -Alk1R3 include one, two, three or more halogen atoms, esepcially fluorine, chlorine or bromine atoms or C1-6alkoxy groups e.g. methoxy or ethoxy, haloC1-6alkoxy groups e.g. xe2x80x94OCF3, substituted amino groups e.g. xe2x80x94NHCH3 or xe2x80x94N(CH3)2 or xe2x80x94COR9 groups e.g. xe2x80x94COCH3 or carboxyl (xe2x80x94CO2H) or esterified carboxyl e.g. xe2x80x94CO2CH3 or xe2x80x94CO2C(CH3)2 groups.
In one most preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) p is the integer 1 and Rz is an optionally substituted aliphatic group -Alk1 R3 as just defined.
In another preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) p is the integer 2 and Rz is an optionally substituted aliphatic group -Alk1 R3 as just defined. Most preferably the Rz groups are identical and especially preferred is the case where the Rz groups are each attached to the same carbon atom of the Cy ring.
In another preferred class of compounds of formulae (1), (2a), (2b), (2c) and (2d) p is the integer 2 and two Rz groups are joined to form a spiro-linked optionally substituted cycloaliphatic group (both Rz groups joined to a single carbon atom of Cy). Especially preferred optionally substituted cycloaliphatic groups of this type include spiro-fused cyclopentyl and cyclohexyl groups. Particularly preferred optional substituents which may be present on such groups include those just described in relation to -Alk1 R3.
A further paticularly useful group of compounds according to the invention has the formula (2e): 
wherein:
Ar1 is an aromatic or heteroaromatic group of formula 
in which W, R16, R17 and g are as previously defined for formula (1);
a is the integer 1 or 2;
b is the integer 1, 2 or 3;
X is a group C(Rw);
and the salts, solvates, hydrates and N-oxides thereof.
In compounds of formula (2e) where Ar1 is an aromatic group of formula (2f) W, R16, R17 and L2 are in partiuclar atoms or groups as particularly described in relation to compounds of formula (2a) hereinbefore.
In compounds of formula (2e) where Ar1 is a heteroaromatic group of formula (2g, (2h) or (2i) R16, g and L2 are in particular atoms or groups as partciularly described in relation to compounds of formula (2b), (2c) and (2d) respectively.
In compounds of formula (2e), Ar2, Alk, R2 and R are in particular atoms or groups as particularly described in relation to compounds of formula (2a).
In one particularly preferred class of compounds of formula (2e) a is the integer 1.
In a most particularly preferred class of compounds of formula (2e) a is the integer 2.
In a further particularly preferred class of compound of formula (2e) b is the integer 1.
In compounds of formula (2e) Rw is preferably an atom or group as generally and particularly described hereinbefore in relation to compounds of formula (2a).
In one preferred class of compounds of formula (2e) p is the integer 1 and Rz is an aliphatic chain -Alk1 R3 as particularly described in relation to compounds of formula (2a).
In another preferred class of compounds of formula (2e) p is the integer 2 and R2 is an aliphatic chain -Alk1 R2 or spiro-linked cycloaliphatic group as particularly described in relation to compounds of formula (2a).
Particularly useful compounds of the invention include:
(S)-3-[4-[(2,6-Naphthyridinyl)amino]phenyl]-2-[(2-(1 -ethylpropyl)-3-oxo-1 -cyclopentenyl)amino]propionic acid;
(S)-3-[4-[(3-Methyl-2,7-naphthyridinyl)oxy]phenyl]-2-((2-propyl-3-oxo-1 -cyclopentenyl)amino]propionic acid;
(S)-3-[(4-[3-Methyl-2,7-naphthyridinyl]oxy)phenyl]-2-[(2-isobutyl-3-oxo-1 -cyclopentenyl)amino]propionic acid;
(S)-3-[(4-(2,7-Naphthyridin-1 -yl)oxy)phenyl]-2-[(2-isobutyl-3-oxo-1 -cyclopentenyl)amino]propionic acid;
(S)-3-[4-[(3, 5-Dichloropyrid4-yl)carboxamido)phenyl]-2-[(2-isobutyl-3-oxo-1-cyclopentenyl)amino]propionic acid;
(S)-3-[4-[(3-Methyl-2,7-naphthyridin-1 -yl)amino]phenyl]-2-[(2-isobutyl-3-oxo-1 -cyclopentenyl)amino]propionic acid;
(S)-3-[4-(-2xe2x80x2,6xe2x80x2-Dimethoxy)biphenyl]-2-[(2-isobutyl-3-oxo-1 -cyclo-pentenyl)amino]propionic acid;
(2 S)-3-[4-(2,6-Naphthyridin-1 -yl)amino)phenyl]-2-[(2-isobutyl-3-oxo-1 -cyclopentenyl)amino]propionate;
(2 S)-3-[4-(2,6-Naphthyridin-1 -yl)am ino)phenyl]-2-[(2-isopropyl-3-oxo-1 -cyclopentenyl)amino]propionic acid
(2 S)-3-[4-(2,6-Naphthyridin-1 -yl)amino)phenyl]-2-[(2-allyl-3-oxo-1 -cyclopentenyl)amino]propionate;
(2 S)-3-[4-(2,6-Naphthyridin-1 -yl)amino)phenyl]-2-[(2-propyl-3-oxo-1 -cyclopentenyl)amino]propionate; and the salts, solvates, hydrates and N-oxides and carboxylic acid ester, particularly methyl, ethyl, propyl and i-propyl esters thereof.
Compounds according to the invention are potent and selective inhibitors of xcex14 integrins. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
The compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders including inflammation in which the extravasculation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders,
Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
For the prophylaxis or treatment of. disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro-fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols Ar1, Ar2, Alk, R1, R2, R3, L1, L2, Alk1, Cy, X, Rx, m, Rz, p, Rw and n when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1999]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. For convenience the processes described below all refer to a preparation of a compound of formula (1) but clearly the description applies equally to the preparation of compounds of formula (2).
Thus according to a further aspect of the invention, a compound of formula (1) in which R is a xe2x80x94CO2H group may be obtained by hydrolysis of an ester of formula (3): 
where Alk represents a group
xe2x80x94CH2CH(CO2Alk10)xe2x80x94, xe2x80x94CHxe2x95x90CH(CO2Alk10)xe2x80x94, or 
[where Alk10 is an alkyl group, for example a C1-6alkyl group]
The hydrolysis may be performed using either an acid or a base depending on the nature of Alk10, for example an organic acid such as trifluoroacetic acid or an inorganic base such as lithium, sodium or potassium hydroxide optionally in an aqueous organic solvent such as an amide e.g. a substituted amide such as dimethylformamide, an ether e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol e.g. methanol at a temperature from ambient to the reflux temperature. Where desired, mixtures of such solvents may be used.
According to a further aspect of the invention a compound of formula (1) may be prepared by condensation of a compound of formula (4): 
where Cy1 is a cycloaliphatic or heterocycloaliphatic ring in which the double bond of the Cy ring of compounds of formula (1) is replaced by a single bond and an oxo (xe2x95x90O) substituent is attached to the carbon atom to which R1R2Nxe2x80x94 will subsequently be joined and X1 is a CH(Rw) or NH group, with an amine R1R2NH or a salt thereof.
The reaction may be performed in an inert solvent or mixture of solvents, for example a hydrocarbon such as an aromatic hydrocarbon e.g. benzene or toluene and/or a halogenated hydrocarbon such as 1,2-dichloroethane, at a temperature from 0xc2x0 C. to the reflux temperature. Where necessary, for example when a salt of an amine R1R2NH is used, an organic base such as diisopropylethylamine can be added.
Any carboxylic acid group present in the intermediate of formula (4) or the amine R1R2NH may need to be protected during the displacement reaction, for example as an ethyl ester. The desired acid may then be obtained through subsequent hydrolysis, for example as particularly described above and generally described below.
A compound of formula (1) may also be prepared by displacement of a leaving group from a compound of formula (5): 
where Ra is a leaving group, with an amine R1R2NH or a salt thereof. Suitable leaving groups represented by Ra include a halogen atom especially a chlorine, bromine or iodine atom, or alkoxy e.g. methoxy or ethoxy or isopropyloxy, alkylthio e.g. methylthio or ethylthio, alkylsulphoxide e.g. methylsulphoxide, aryloxy e.g. dinitrophenyloxy or araalkoxy e.g. benzyloxy group.
The reaction may be performed in an inert solvent or mixture of solvents for example a substituted amide such as dimethylformamide, or alcohol such as methanol or ethanol and/or a halogenated hydrocarbon such as dichloromethane, at a temperature from 0xc2x0 C. to the reflux temperature.
Where necessary, for example when the salt of an amine R1R2NH is used an organic base such as diisopropylethylamine can be added.
Where desired the displacement reaction may also be performed on an intermediate of formulae (4) or (5) or R1R2NH which is linked, for example via its R1 or R3 group, to a solid support, such as a polystyrene resin. After the reaction the desired compound of formula (1) may be displaced from the support by any convenient method, depending on the original linkage chosen.
Intermediates of formulae (4), (5) and R1R2NH may be obtained from simpler, known compounds by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formulae (1) and (2) where appropriate functional groups exist in these compounds.
Thus compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation. For example, compounds containing a -L1H or -L2H group (where L1 and L2 is each a linker atom or group) may be treated with a coupling agent R3(Alk1 )nX1 or Ar1X1 respectively in which X1 is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g. p-toluenesulphonyloxy group.
The reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, or an organic amine e.g. triethylamine or N,N-diisopropylethylamine or a cyclic amine, such as N-methylmorpholine or pyridine, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran.
Compounds of formula Ar1X1 may be prepared from alcohols of formula Ar1OH by reaction with a halogenating agent, for example a phosphorous oxyhalide such as phosphorous oxychloride at an elevated temperature e.g. 110xc2x0 C.
Intermediate alcohols of formula Ar1OH in which, for example, Ar1 represents a 2,6-naphthyridine may be prepared by methods well known to a person skilled in the art, e.g. by the method of Sakamoto,T. et al (Chem. Pharm. Bull. 33, 626-633, (1985)].
Alternatively alkylating agents of formula Ar1X1 in which, for example, Ar1 represents a 2,6-naphthyridine may be prepared by reaction of a 2,6-naphthyridine N-oxide or N, Nxe2x80x2-dioxide with a halogenating agent, e.g. a phosphorous oxyhalide such as phosphorous oxychloride to give a 1-halo or 1,5-dihalo-2,6-napthyridine respectively. In the case of 1,5-dihalo-2,6-napthyridines each halogen atom may be substituted separately by a reagent such as HL2Ar2AlkN(R2)H or HL3(Alk2)tL4(R4)u by the particular methods just described above.
2,6-Napthyridine N-oxides and N,Nxe2x80x2-dioxides may be generated from the corresponding 2,6-napthyridines by the general methods of synthesis of N-oxides described below or they may be synthesised by the methods of Numata, A. et al (Synthesis, 1999, 306-311).
Further alkylating agents of formula Ar1X1 in which, for example, Ar1 represents a 2,6-naphthyridine, may be prepared by the methods of Giacomello G. et al [Tetrahedron Letters, 1117-1121 (1965)], Tan, R. and Taurins, A. [Tetrahedron Lett., 2737-2744, (1965)], Ames, D. E. and Dodds, W. D. [J. Chem. Soc. Perkin 1, 705-710 (1972)] and Alhaique, F. et al [Tetrahedron Lett., 173-174 (1975)].
Intermediate alcohols of formula Ar1OH in which Ar1 represents an optionally substituted 2,7-naphthyridin-1-yl group may be prepared by methods well known to a person skilled in the art, e.g. by the method of Sakamoto,T. et al [Chem. Pharm. Bull. 33, 626-633, (1985)] or Baldwin, J, J. et al [J. Org. Chem, 43, 4878-4880, (1978)]. Thus for example the method of Baldwin may be modified to allow the synthesis of intermediate 3-substituted 2,7-naphthyridin-1 -yl groups of formula Ar1 OH as depicted in Scheme 1: 
Reaction of an optionally substituted 4-methyl-3-cyano pyridine of formula (6) with a N,N-dimethylformamide di-C1-6alkyl acetal, e.g. N,N-dimethyl-formamide diethyl acetal, in a dipolar solvent such as an amide e.g. a substituted amide such as dimethylformamide at an elevated temperature e.g. 140-150xc2x0 gives a compound of formula (7) or (8) or a mixture thereof depending on the nature of the group R16.
Compounds of formula (7) or (8) may be cyclised to 3-substituted 2,7-naphthyridin-1-yl alcohol of formula (9) by treatment with an acid e.g. an inorganic acid such as hydrochloric acid or hydrobromic acid or an acidic gas such as hydrogen chloride gas in an organic solvent e.g. an organic acid such as acetic acid optionally in the presence of water at a temperature from about ambient to 50xc2x0 C.
Alternatively alkylating agents of formula Ar1X1 in which Ar1 represents an optionally substituted 2,7-naphthyridin-yl group may be prepared by reaction of a 2,7-naphthyridine N-oxide or N, Nxe2x80x2-dioxide with a halogenating agent, e.g. a phosphorous oxyhalide such as phosphorous oxychloride to give a 1-halo or 1,6-dihalo- and/or-1,8-dihalo-2,7-napthyridine respectively. In the case of 1,6-dihalo-and/or 1,8-dialo-2,6-napthyridines each halogen atom may be substituted separately by a reagent such as HL2Ar2AlkN(R2)H or HL3(Alk2)tL4(R4)u by the particular methods just described above.
2,7-Napthyridine N-oxides and N,Nxe2x80x2-dioxides may be generated from the corresponding 2,7-napthyridines by the general methods of synthesis of N-oxides described below or they may be synthesised by the methods of Numata, A. et al (Synthesis, 1999, 306-311).
Further alkylating agents of formula Ar1X1 in which, for example, Ar1 represents a 2,7-naphthyridin-1-yl, may be prepared by the methods of Wenkert E. et al J. Am. Chem. Soc. 89, 6741-5 (1967), and Aust. J. Chem. 433 (1972), and Sheffield D. J. J. Chem. Soc. Perkin. Trans I, 2506 (1972).
Intermediate alcohols of formula Ar1 OH in which Ar1 represents a 3-substituted isoquinolin-1-yl group may be prepared by methods well known to a person skilled in the art, e.g. by the methods of Wu M.-J. et al Tetrahedron, 55, 13193-200 (1999), Hiebl J. et al Tetrahedron Lett. 40, 7935-8 (1999), Nagarajan A. et al Indian J. Chem., Sect. B, 28B, 67-78 (1989), Brun E. M. et al Synlett, 7, 1088-90 (1999) and Brun, E. M. et al Synthesis, 273-280 (2000).
Further alkylating agents of formula Ar1X1 in which, for example, Ar1 represents a isoquinolin-1-yl group, may be prepared by the methods of Falk H. et al Monatsch. Chem. 25, 325-33 (1994), and Deady, L. W. et al Aust. J. Chem 42, 1029-34 (1989).
In a further example intermediates of formula R1 R2NH may be obtained by reaction of a compound of formula Ar1 L2H with a compound of formula X1Ar2AlkN(R2)H under the reaction conditions just described
Compounds of formula Ar1L2H in which, for example Ar1 represents a 2,6-naphthyridine and L2 is a xe2x80x94N(R8)xe2x80x94 group, may be prepared from substituted 4-cyano-3-cyanomethylpyridines by the methods of Alhaique, F. et al (ibid and Gazz. Chim. Ital. 1975, 105, 1001-1009) or from 3-fomylpyridines by the methods of Molina, P. at al (Tetrahedron 1992, 48, 4601-4616).
Compounds of formula Ar1L2H in which, for example Ar1 represents a 2,7-naphthyridin-1 -yl group and L2 is a xe2x80x94N(R8)xe2x80x94 group, may be prepared from substituted 4-formylpyridines by the methods of Molina, P. et al Tetrahedron, 48, 4601-4616, (1992), or by the methods described in U.S. Pat. No. 3,938,367.
Compounds of formula Ar1L2H in which, for example Ar1 represents a 3-substituted isoquinolin-1-yl group and L2 is a xe2x80x94N(R8)xe2x80x94 group, may be prepared by the methods of Bordner, J. et al J. Med. Chem. 31, 1036-9 (1988), Tovar J. D. et al J. Org. Chem., 64, 6499-6504 (1999), Karser E. M. et al Synthesis, 11, 805-6 (1974), and Molino, P et al J. Chem. Soc. Perkin Trans. 1 1727-31 (1990).
In another example, compounds containing a -L1 H or -L2H or group as defined above may be functionalised by acylation or thioacylation, for example by reaction with one of the alkylating agents just described but in which X1 is replaced by a xe2x80x94C(O)X2, xe2x80x94C(S)X2, xe2x80x94N(R8)COX2 or xe2x80x94N(R8)C(S)X2 group in which X2 is a leaving atom or group as described for X1. The reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or N-methyl-morpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachioride or an amide, e.g. dimethyl-formamide, at for example ambient temperature. Alternatively, the acylation may be carried out under the same conditions with an acid (for example one of the alkylating agents described above in which X1 is replaced by a xe2x80x94CO2H group) in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,Nxe2x80x2-dicyclohexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1 -hydroxybenzotriazole. Alternatively the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to the desired acylation reaction
In a further example compounds may be obtained by sulphonylation of a compound containing an xe2x80x94OH group by reaction with one of the above alkylating agents but in which X1 is replaced by a xe2x80x94S(O)Hal or xe2x80x94SO2Hal group [in which Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
In another example, compounds containing a -L1 H or -L2H group as defined above may be coupled with one of the alkylation agents just described but in which X1 is replaced by an xe2x80x94OH group in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl-or dimethylazodicarboxylate.
In a further example, ester groups xe2x80x94CO2R5, xe2x80x94CO2R11 or xe2x80x94CO2Alk7 in the compounds may be converted to the corresponding acid [xe2x80x94CO2H] by acid-or base-catalysed hydrolysis depending on the nature of the groups R5, R11 or Alk7. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a further example, xe2x80x94OR5 or xe2x80x94OR14 groups [where R5 or R14 each represents an alkyl group such as methyl group] in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
Alcohol [xe2x80x94OH] groups may also be obtained by hydrogenation of a corresponding xe2x80x94OCH2R14 group (where R14 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, xe2x80x94OH groups may be generated from the corresponding ester [CO2Alk7 or CO2R5] or aldehyde [xe2x80x94CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol xe2x80x94OH groups in the compounds may be converted to a corresponding xe2x80x94OR5 or xe2x80x94OR14 group by coupling with a reagent R50H or R14OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NHR3 or xe2x80x94NHSO2NHAr1] groups in the compounds may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with a sulphamide R3NHSO2NH2 or Ar1NHSO2NH2 in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In another example compounds containing a xe2x80x94NHCSAr1, xe2x80x94CSNHAr1, xe2x80x94NHCSR3 or xe2x80x94CSNHR3 may be prepared by treating a corresponding compound containing a xe2x80x94NHCOAr1, xe2x80x94CONHAr1, xe2x80x94NHCOR3 or xe2x80x94CONHR3 group with a thiation reagent, such as Lawesson""s Reagent, in an anhydrous solvent, for example a cyclic ether such as tetrahydrofuran, at an elevated temperature such as the reflux temperature.
In a further example amine (xe2x80x94NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around xe2x88x9278xc2x0 C., in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
In another example, sulphur atoms in the compounds, for example when present in a linker group L1 or L2 may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
In another example compounds of formula Ar1X1 (where X1 is a halogen atom such as a chlorine, bromine or iodine atom) may be converted to such compounds as Ar1CO2R20 (in which R20 is an optionally substituted alkyl, aryl or heteroaryl group), Ar1 CHO, Ar1CHCHR20, Ar1CCR20, Ar1N(R20)H, Ar1N(R20)2, for use in the synthesis of for example compounds of formula Ar1L2Ar2AlkN(R2)H, using such well know and commonly used palladium mediated reaction conditions as are to be found in the general reference texts Rodd""s Chemistry of Carbon Compounds, Volumes 1-15 and Supplementals (Elsevier Science Publishers, 1989), Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed. Katritzky et al, Volumes 1-8, 1984 and Volumes 1-11, 1994 (Pergamon), Comprehensive Organic Functional Group Transformations, Ed. Katritzky et al, Volumes 1-7, 1995 (Pergamon), Comprehensive Organic Synthesis, Ed. Trost and Flemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia of Reagents for Organic Synthesis, Ed. Paquette, Volumes 1-8 (John Wiley and Sons, 1995), Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989) and March""s Advanced Organic Chemistry (John Wiley and Sons, 1992).
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
The following Examples illustrate the invention. All temperatures are in xc2x0 C. The following abbreviations are used:
All NMR""s were obtained at 300 MHz and 400 MHz.
Intermediate 1
2-Benzyl-1,3-cyclopentanedione
To a suspension of 1,3-cyclopentanedione (500 mg, 5.10 mmol) and anhydrous lithium iodide (750 mg, 5.61 mmol) in acetonitrile (10 ml) was added DBU. After 30 min benzyl bromide (1.74 g, 10.2 mmol) was added and the reaction heated for 24 h at reflux. The reaction was poured into water (40 ml ), extracted with EtOAc (4xc3x9750 ml), dried (MgSO4), the solution concentrated in vacuo and the residue purified by chromatography (SiO2; EtOAc) to give the title compound as an off white solid (222 mg, 23%). xcex4H (CD3OD) 7.20 (4H, d), 7.10 (1H, m), 3.41 (2H, s), 2.52 (4H, s). m/z (ESI, 70V) 189 (MH+).
Intermediate 2
2-Allyl-1,3-cyclopentanedione
Prepared in a similar manner to Intermediate 1, from 1,3-cyclopentanedione and alkyl bromide, heating to reflux for 3 days to give the title compound as an refluxing for 3 d with allyl bromide off-white solid (115 mg, 8%). xcex4H (CD3OD) 5.80 (1H, m), 5.00-4.80 (2H, 3xc3x97m), 2.85 (2H, d), 2.48 (4H, s). m/z (ESI, 70V) 139 (MH+).
Intermediate 3
2-Butyl-1,3-cyclopentanedione
To a suspension of cyclopent-4-ene-1,3-dione (1.22 g, 12.6 mmol) in acetic anhydride (4 ml) were added ethyl orthobutyrate (3.74 g, 25.3 mmol) and anhydrous ZnCl2. The reaction was heated at 80xc2x0 for 24 h, solid removed by filtration, the filtrate concentrated in vacuo and the residues purified by chromatography (SiO2; 70:30 hexane/EtOAc) to give 2-(xcex1-methoxypropyl idene)cyclopent4-ene-1,3-dione as a brown oil. xcex4H (CDCl3) 6.88 (2H, s), 4.07 (3H, s), 3.00 (2H, t), 1.63 (2H, m), 1.08 (3H, t). m/z (ESI, 70V) 181 (MH+).
A solution of this oil (EtOH, 11 ml) was subjected to catalytic (Pd/C, 200 mg) hydrogenation for 24 h, filtered, the solution concentrated in vacuo, and the residue purified by chromatography (SiO2; EtOAc) to give the title compound as a white, waxy solid (494 mg, 25%). xcex4H (CD3OD) 2.46 (4H, s), 2.09 (2H, t, J 7.3 Hz), 1.33 (4H, m), 0.89 (3H, t, J 9.5 Hz). m/z (ESI, 70V) 155 (MH+).
Intermediate 4
2-Phenyl-1,3-Cyclopentanedione
To a solution of BF3.OEt2 (1.3 g, 9.2 mmol) and benzaldehyde diemethylacetal (1.0 g, 6.6 mmol) in DCM (5 ml) under N2 at xe2x88x9278xc2x0 was added a solution of 1,2-bistrimethylsilyloxycyclobutene (1.4 g, 6.1 mmol) in DCM (3 ml) maintaining a temperature of less than xe2x88x9270xc2x0. After 3 h at xe2x88x9278xc2x0 C. the solution was poured into saturated NaHCO3 solution (40 ml), extracted into DCM, washed (NaHCO3xc3x971, H2Oxc3x971), dried (MgSO4), the solution concentrated in vacuo and the residue distilled (170xc2x0, 0.4 mm Hg) to give 1.1 g of clear liquid. To this liquid was added TFA (20 ml) and the solution heated at reflux for 15 min. The solvent was removed in vacuo, the residue slurried in Et2O and the off-white solids isolated by filtration and dried to give the title compound (760 mg, 72%). xcex4H (d6-DMSO) 7.80 (2H, d, J 8.4 Hz), 7.31 (2H, t), 7.16 (1H, t, J 7.35 HZ), 2.51 (4H, s). m/z (ESI, 70V) 175 (MH+).
Intermediate 5
2-Propyl-1,3-Cyclopentanedione
To a solution of BF3.OEt2 (1.30 g, 9.2 mmol) and butyraldehyde (0.40 g, 5.5 mmol) in DCM (5 ml) under N2 at xe2x88x9278xc2x0 was added a solution of 1,2-bis trimethylsilyloxycyclobutene (1.4 g, 6.1 mmol) in DCM (3 ml) maintaining a temperature of less than xe2x88x9270xc2x0. After 2 h at xe2x88x9278xc2x0 the solution was poured into saturated NaHCO3, extracted into EtOAc, washed (brine), dried (MgSO4) and the solution concentrated in vacuo to yield a clear liquid. To this liquid was added TFA (20 ml) and the solution heated at reflux for 24 h. The solution was concentrated in vacuo and the residue purified by chromatography (SiO2, 50:50 EtOAc/hexane) to yield the title compound as an off-white solid (140 mg, 18%). xcex4H (CD3OD) 2.46 (4H, s), 2.07 (2H, t, J 7.5 Hz), 1.40 (2H, m), 0.86 (3H, t, J 7.4 Hz). m/z (ESI, 70V) 141 (MH+).
Intermediate 6
2-Isopropyl-1,3-cyclopentanedione
To a solution of TiCl4 (1.47 g, 7.77 mmol) and isobutyraldehyde (559 mg, 7.75 mmol) in DCM (16 ml) under N2 at xe2x88x9278xc2x0 was added a solution of 1,2-bistrimethylsilyloxycyclobutene (1.97 g, 8.56 mmol) in DCM (16 ml) maintaining a temperature of less than xe2x88x9270xc2x0. After 30 min the reaction was poured into water, extracted into DCM, washed (H2Oxc3x972), dried (MgSO4) and the solution concentrated in vacuo to yield a clear oil. To this oil was added TFA (20 ml) and the solution heated at reflux for 24 h. The solution was concentrated in vacuo and the residue purified by chromatography (SiO2; 50:50 EtOAc/hexane) to give the title compound as an off-white solid (180 mg, 17%). xcex4H (d6-DMSO) 2.61 (1H, sept, J 7.0 Hz), 2.29 (4H, s), 1.04 (6H, d, J 7.0 Hz). m/z (ESI, 70V) 141 (MH+).
Intermediate 7
2-Isobutyl-1,3-cyclopenentanedione
To a stirring mixtue of silica gel (45 g) isobutyraldehyde (375 mg, 5.20 ) and 4-methylbenzenethiol (3.80 g, 30.6 mmol) in DCM (15 ml) was addd 1,3-cyclopentanedione (300 mg, 3.06 mmol). The suspension was stirred for 24 h, the solvent removed in vacuo, the residues dry packed onto the top of a silica column and the column run with gradient elution (SiO2; 100:0 -50:50 Hexane/EtOAc) to give a thiol trapped intermediate as a white solid (400 mg, 47%),. To this intermediate (300 mg, 1.09 mmol) in MeOH (5 ml) was added NaCNBH3 (55 mg, 0.8 mmol), the reaction stirred for 24 h and quenched with water. The solution was concentrated in vacuo and the residue purified by chromatography (SiO2: 50:50, EtOAc/hexane) to give the title compound as an off-white solid (80 mg, 28% overall). xcex4H (CD3OD) 2.43 (4H, s), 1.96 (2H, d, J 7.1 Hz), 1.77 (1H, sept, J 6.6 Hz), 0.83 (6H, d, J 6.6 Hz). m/z (ESI, 70V) 155 (MH+).
Intermediate 8
2-(1-Ethylpropyl)-1,3-cyclopentanedione
Prepared in a similar manner to intermediate 6 from 2-ethylbutyraldehyde xcex4H (CD3OD) 2.46 (4H, s), 2.30 (1H, m), 1.67 (2H, m), 1.52 (2H, m), 0.76 (6H, t, J 7.4 Hz). m/z (ESI, 70V) 169 (MH+).
Intermediate 9
2-Cyclohexyl-1,3-cyclopentanedione
To a suspension of 1,3-cyclopentandedione (4.00 g, 0.040 mmol) in water (30 ml) were added LiOH.H2O (1.88 g, 0.045 moll) and 3-bromocyclohexene (7.18 g, 0.045 mmol). The solution was stirred overnight, the pH raised to 12-14 (LiOH.H2O) and stirred for 2 h. The solution was washed with Et2O (4xc3x9740 ml), acidified to pH 1-2 and resulting solids isolated by filtration, washed and dried to give 2-cyclohexene-1,3-cyclopentanedione. [xcex4H (CD3OD) 5.69 (1H, m), 5.44 (1H, m), 3.20 (1H, m), 2.47 (4H, s), 2.15-1.19 xcx9c(6H, m). m/z ESI, 70V) 179 (MH+)]. The product was dissolved in EtOH (50 ml) and reduced under an atmosphere of H2 at RT with Pd/C (200 mg). After 5 h the reaction was filtered and the solvent removed to give the title compound as a white solid (890 mg 12%). xcex4H (CD3OD) 2.44 (4H, 2), 2.39 (1H, m), 1.85-1.70 (5H, m), 1.50-1.45 (2H, m), 1.35-1.15 (3H, m). m/z (ESI, 70V) 181 (MH+).
Intermediate 10
4-(2-(N,N-Dimethylamino)ethylen-1-yl)-3-cyanopyridine
A solution of 4-methyl-3-cyanopyridine (prepared acccording to Ref: J. Prakt. Chem. 338. 663 (1996), 8.0 g, 67.8 mmol) and N,N-dimethylformamide diethyl acetal (11.0 g, 74.8 mmol) in dry DMF (50 ml) was stirred at 140xc2x0 under N2 for 2 days. An additional portion of N,N,-dimethylformamide diethyl acetal (5 g) was added and stirred at 140xc2x0 for 4 h. The volatiles were removed in vacuo and the obtained dark oil partitioned between EtOAc (300 ml) and water (50 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3xc3x97100 ml). The combined organic extracts were washed with brine (30 ml), dried (Na2SO4), treated with activated charcoal, filtered and evaporated in vacuo to afford essentially pure title compound as a dull orange solid (10.1 g, 85%). xcex4H (CDCl3) 8.49 (1H, s), 8.25 (1h, d, J 5.9 hz), 7.29 (1H, d, J 13.2 Hz), 7.09 (1H, d, J 5.9 Hz), 5.25 (1H, d, J 13.2 Hz) and 2.99 (6H, s); m/z (ES+, 70V) 174 (MH+).
Intermediate 11
1-Hydroxy-2,7-naphthyridine hydrochloride salt
HCl gas was bubbled through a stirred solution of Intermediate 10 (6.2 g, 3.58 mmol) in glacial acetic acid (50 ml) and water (0.64 ml, 3.55 mmol) for 1-2 min. The reaction mixture was stirred in a stoppered flask at 40xc2x0 for 18 h. The volatiles were removed in vacuo affording a dark residue, which was treated with water (3xc3x9720 ml) and re-evaporated in vacuo. The obtained dark semi-solid was treated with 40 ml warm ethanol, ice-cooled, and the undissolved solid collected by filtration affording the title compound as a green coloured solid (5.2 g, 80%) xcex4H (DMSO-D6) 12.5 (1H, br s), 9.38 (1H, s), 8.84 (1H, d, J 7.0 Hz), 8.15 (1H, d, J 7.0 Hz), 7.89 (1H, br dd, J 7.0, 5.0 Hz) and 6.85 (1H, d, J 7.0 Hz); m/z (ES+, 70V), 147 (MH+).
Intermediate 12
1-Chloro-2,7-naphthyridine
Intermediate 11 (5.2 g, 28.5 mmol) was stirred with phosphorous oxychloride (75 ml) at 110xc2x0 for 24 h. The volatiles were removed in vacuo affording a dark oil which was poured into an ica-bath cooled mixture of saturated aqueous NaHCO3 (100 ml containing 20 g solid NaHCO3) and EtOAc (100 ml). After thorough mixing the phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9775 ml). The combined organic extracts were washed with brine (15 ml), dried (Na2SO4) and evaporated in vacuo to afford the title compound as a yellow solid (4.0 g, 85%) xcex4H (CDCl3) 9.45 (1H, s), 8.81 (1H, d, J 5.7 HZ), 8.47 (1H, d, J 5.7 Hz), 7.66 (1H, d, J 5.7 Hz) and 7.60 (1H, d, J 5.7 HZ); m/z (ES+, 70V) 165 and 167 (MH+).
Intermediate 13
Ethyl (S)-3-[4-2,7-naphthyridin-1-ylamino)phenyl]-2-amino propanoate
A solution of ethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino] propanoate (638 mg, 2.07 mmol) and Intermediate 12 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml) was stirred at 120xc2x0 for 15 min and at 100xc2x0 for 1 h under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (10 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9730 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dark foam. Chromatography (SiO2; 5 to 10% MeOH/DCM) afforded a mixture of ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl) amino]propanoate and some of the title compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (75 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3xc3x9730 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid. Chromatography (silica; 10% MeOH/DCM) afforded the title compound as a straw-coloured solid (420 mg, 60% over two steps). xcex4H (CDCl3) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
Intermediate 14
Ethyl (S)-3-[4-(2,7-naphthyridin-1-yloxy)phenyl]-2-aminopropanoate
A mixture of N-(BOC)-(S)-tyrosine ethyl ester (1.79 g, 5.80 (mmol) potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 12 (1.0 g, 6.08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h, and at 40xc2x0 for 18 h. The DMF was removed in vacuo and the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9720 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a new colourless oil. Chromatography (silica; 2.5% MeOH/DCM) afforded reasonably pure N-t-butoxycarbonyl protected title compound (1.81 g, 71%). This material was dissolved in EtOAc (40 ml) and HCl gas was bubbled through the stirred solution for 1 min. then the mixture was stirred for an additional 0.5 h. The volatiles were removed in vacuo affording a yellow solid which was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9720 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained oil was chromatographed (silica; 5% MeOH/DCM) to afford the title compound as a near colourless oil (0.87 g, 62%) xcex4H (CDCl3) 9.77 (1H, s), 8.75 (1H, d, J. 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25 (1 H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 4.22 (2H, q, J 7/1 Hz), 3.80-3.70 (1H, obscured m), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) 1.30 (3H, t, J 7.1 Hz) and 0.78 (2H, br s); m/z (ES+, 70V) 324 (MH+).
Intermediate 15
4-Acetonyl-3-cyanopyridine
A solution of 4-methyl-3-cyanopyridine (4 g, 33.9 mmol) and N,N-dimethylacetamide dimethylacetyl (5.4 g, 40.6 mmol) in dry DMF (20 ml) was stirred at 130xc2x0 for 7 h. The volatiles were removed in vacuo to afford a dark oil which solidified on standing. This material was chromatographed (silica; 50% EtOAc/Hexane-100% EtOAc) affording the title compound as an off-yellow solid (3.73 g, 69%). xcex4H (CDCl3) 8.87 (1H, s), 8.74 (1H, d, J 5.2 Hz), 7.28 (1H, d, J 5,2 Hz), 4.00 (2H, s) and 2.36 (3H, s); m/z (ES+, 70V) 161 (MH+).
Intermediate 16
1-Hydroxy-3-methyl-2,7-naphthyridine hydrochloride
HCl gas was bubbled through a stirred solution of Intermediate 15 (3.73 g, 23.3 mmol) in glacial acetic acid (40 ml) for several minutes. The flask was stoppered and reaction stirred for 18 h at ambient temperature. The volatiles were removed in vacuo affording a straw-coloured solid. This was twice treated with water (30 ml portions) and re-evaporated in vacuo to dryness, affording the title compound (contaminated with xcx9c25% unidentified by-product) as a dark straw coloured solid (4.1 g). xcex4H (DMSO-d6) 12.46 (1H, br s), 9.32 (1H,s ), 8.71 (1H, d, J 6.5 Hz), 7.98 (1H, d, J 6.5 Hz), 6.67 (1H,s) and 2.38 (3H, s); m/z (ES+, 70V) 161 (MH+). Used without further purification.
Intermediate 17
1-Chloro-3-methyl-2,7-naphthyridine
Intermediate 16 (4.1 g) was treated with phosphorus oxychloride (50 ml) at 130xc2x0 for 3 h, affording a dark solution. The volatiles were removed in vacuo and the obtained dark oil extracted with Et2O (100 ml). Saturated aqueous NaHCO3 (ice cold; containing 10 g additional solid NaHCO3) was poured (with CARE!) onto the crude product with swirling and ice-bath cooling. After thorough shaking, addition Et2O (80 ml) was added, the mixture re-shaken, and the phases separated. The aqueous layer was re-extracted with Et2O (2xc3x9780 ml) and the combined ethereal extracts washed with brine (20 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid (3.6 g). Chromatography (silica; 70% EtOAc/Hexane - 100% EtOAc) afforded a more-polar by-product (3-methyl-1H-pyrano[3,4-C]pyridin-1-one, (0.7 g) and the title compound as a white solid (2.82 g, 79% from intermediate 7) xcex4H (CDCl3) 9.66 (1 H, s), 8.73 (1H, d, J 5.8 hz), 7.56 (1H, d, J 5.8 Hz), 7.40 (1H, s) and 2,69 (3H, s); m/z (ES+, 70V) 179 and 181 (MH+).
Intermediate 18
Ethyl (S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[N-(tertbutyloxycarbonyl) amino]propanoate hydrochloride
Acetylchloride (55 mg, 50 xcexcl, 0.70 mmol) was added to absolute ethanol (25 ml) and stirred for one minute. Intermediate 17 (2.50 g, 14.0 mmol) and ethyl-(S)-3-[4-aminophenyl]-{tert-butyloxycarbonyl]propanoate (4.31 g, 14.0 mmol) were added and the reaction mixture stirred at 60xc2x0 for 2.75 h. The volatiles were removed in vacuo to afford a yellow-orange solid. This was treated with EtOAc (xcx9c25 ml), warmed, re-cooled and the precipitate collected by filtration, with Et2O washing, affording the title compound as yellow solid (4.96 g, 73%). xcex4H (CDCl3) 10.44 (1 h, br s), 10.33 (1H, br s), 8.60 (1H, d, J 6.5 Hz), 8.00 (1H, d, J 6.5 Hz), 7.85 (2H, d, J 8.5 Hz), 7.28 (1H, d, J 8.0 Hz), 7.23 (2H, d, J 8.5 Hz), 7.16 (1H,s ), 4.19-4.01 (1H, m), 4.08 (2H, q, J 7.0 Hz), 2.97 (1H, dd, J 13.8, 5.4 Hz), 2.86 (1H, dd, J 13.8, 10.0 Hz), 2.50 (3H,s ), 1.34 (9H, s) and 1.15 (3H, t, J 7.0 Hz); m/z (ES+, 70V)451 (MH+).
Intermediate 19
Ethyl-(S)-3-[4-(3-methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-aminopropanoate
HCl gas was bubbled through a stirred solution of Intermediate 18 (4.95 g, 10.2 mmol) for 1-2 min. After 30 min stirring at ambient temperature the volatiles were removed in vacuo affording a yellow powder. This was treatd with saturated aqueous NaHCO3 (30 ml) then extracted with EtOAc (100 ml, and 3xc3x9750 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo affording the title compound as a yellow solid (3.56, 100%). xcex4H (CDCl3) 9.25 (1H, s), 8.50 (1H, d, J 5.6 Hz), 7.66 (2H, d, J 8.4 Hz), 7.35 (1H, d, J 5.6 Hz), 7.34 (1H, masked s), 7.14 (2H, d, J 8.4 Hz), 6.81 (1H, s), 4.12 (2H, q, J 7.2 Hz), 3.65 91H, dd, J 7.8, 5.2 Hz), 3.02 (1H, dd, J 13.7, 5.2 Hz), 2.80 (1H, dd, J 13.7, 7.8 Hz), 2.48 (3H, s), 1.56 (2H, br s) and 1.21 (3H, t, J 7.2 Hz); m/z (ES+, 70V) 351 (MH+).
Intermediate 20
Ethyl (S)-3-[4-(3-methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(N-t-butyloxycarbonylamino)-propanoate
A mixture of N-tbutyloxycarbonyl-(S)-tyrosine ethyl ester (14.5 g, 46.9 mmol), caesium carbonate (14.05 g,43.1 mmol) and Intermediate 17 (7.0 g, 39.2 mmol) in dry DMF (60 ml) was stirred at room temperature for 48 h. The reaction was diluted with Et2O (150 ml) and filtered off. The filtrate was evaporated under high vacuum and the residue was chromatographed (SiO2; 40% - 60% EtOAc/Hexane) which afforded the title compound as a viscous, straw-coloured oil (16.2 g, 77%) xcex4H (CDCl3) 9.56 (1H, s), 8.58 (1H, d, J 5.8 Hz), 7.39 (1H, d, J 5.8 Hz), 7.15-7.10 (4H, m), 7.00 (1H, s), 4.99-4.91 (1H,m), 4.54-4.46 (1H, m), 4.09 (2H, q, J 7.1 Hz), 3.10-2.99 (2H,m), 2.36 (3H, s), 1.34 (9H, s) and 1.15 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 452 (MH+).
Intermediate 21
Ethyl (S)-3-[4-(3-methyl-2,7-naphthyrdin-1-yloxy)phenyl]-2-aminopropanoate
HCl gas was bubbled through a stirred solution of Intermediate 20 (16 g) in EtOAc (300 ml) until a persistent fine white precipitate formed (xcx9c2 minutes). After stirring for 0.5 h the volatiles were removed in vacuo. The obtained solid was partitioned between EtOAc (250 ml) and saturated aqueous NaHCO3 (80 ml plus 5 g solid NaHCO3). The phases were separated and the aqueous layer re-extracted with EtOAc (5xc3x9750 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an oil Chromatography (SiO2; 100% EtOAC - 10% EtOH/EtOAc) afforded the title compound as a viscous oil (11.1 g, 89%). xcex4H (CDCl3) 9.71 (1H,s ), 8.70 (1H, d, J 5. Hz), 7.50 (1H, d, J 5.8 Hz), 7.31-7.28 (4H,m), 7.11 (1H, s), 4.23 (2H, q, J 7.1 Hz), 3.79-3.72 (1H, m), 3.14 (1H, dd, J 14.1, 5.4 Hz), 2.94 (1H, dd, J 14.1, 7.8 Hz), 2.47 (3H, s), 1.75-1.50 (2H, br s) and 1.30 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 352 (MH+).
Intermediate 22
Methyl (2S)-2-](tert- butoxycarbonyl)amino]-3-(4-{[trifluoromethylsulphonyl]oxy}phenyl)propanoate
Triflic anhydride (5.05 ml, 30 mmol) was added to a mixture of N-BOC tyrosine methyl ester (7.38 g, 25 mmol) and pyridine (10 ml, 125 mmol) in DCM (40 ml) at 0xc2x0. After 45 min at 0xc2x0 water (80 ml) and DCM (100 ml) were added. The organic phase was washed with NaOH aq. (0.5M, 60 ml), water (60 ml), citric acid (10%, 2xc3x9780 ml) and water (60 ml), dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow oil which solidified on standing (10.6 g). xcex4H (CDCl3) 7.26-7.18 (4H, m), 5.05 (1H, v br d), 4.59 (1H, v br q), 3.70 (3H, s), 3.16 (1H, dd, J 13.7, 5.7 Hz), 3.02 (1H dd, J 13.8, 6.5 Hz), 1.40 (9H, s); m/z (ES+, 70V) 450 (M++Na).
Intermediate 23
Methyl (2S)-2-[tert-butoxycarbonyl)amino]-3-(4-]2xe2x80x2,6xe2x80x2-dimethoxy]biphenylyl)propanoate
A mixture of the Intermediate 22 (4.27 g, 10 mmol), 2,6-dimethoxybenzene boronic acid (4.55 g, 25 mmol), potassium carbonate (6.9 g, 50 mmol) tetrakis(triphenylphosphine)palladium(0) (2.31 g) in DME (45 ml) and water (5 ml) was heated at 80xc2x0 overnight. The mixture was diluted with EtOAc, washed with dilute HCl, NaHCO3 (aq.), water and brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2; EtOAc/hexane, 20:80-30:70) gave the title compound (2.27 g). xcex4H (DMSO-d6) 7.33 (1H, d, J 8.2 Hz), 7.27 (1H, t, J 8.3 Hz), 7.20 (2H, d, J 8.1 Hz), 7.10 (2H, d, J 8.0 Hz), 6.71 (2H, d, J 8.4 Hz), 4.2 (1H, m), 3.63 (9H, s), 3.01 (1H, dd, J 13.9, 4.5 Hz), 2.84 (1H, dd, J 13.7, 10.3 Hz), 1.34 (9H, s); m/z (ES+, 70V) 438 (M++Na).
Intermediate 24
Methyl (2S)-2-amino-3-(4-[2xe2x80x2,6xe2x80x2-dimethoxy]biphenylyl)propionate hydochloride
Anhydrous HCl was bubbled through a solution of Intermediate 23 (1.30 g, 3.13 mmol) in EtOAc (30 ml) for a few seconds. The mixture was stirred at room temperature for 1 h. Some solvent was removed in vacuo until material began to precipitate. The precipitate was filtered off and dried to give the title compound as pale yellow crystals (888 mg, 81%). xcex4H (DMSO-d6) 8.7 (2H, br s), 7.28 (1H, t, J 8.4 Hz), 7.21 (2H, d, J 8.4 Hz), 7.17 (2H, d, J 8.3 Hz), 6.73 (2H, d, J 8.4 Hz), 4.30 (1H, t, J 6.6 Hz), 3.69 (3H, s), 3.64 (6H, s), 3.18 (1H, dd, J 14.1, 6.2 Hz), 3.10 (1H, dd, J 14.1, 7.1 Hz); m/z (ES+, 70V) 316 (MH+).
Intermediate 25
Ethyl N-(diphenylmethylene)-2-amino-3-(5-benzenesulphonyloxy-pyrid-2-yl)propionate
A solution of ethyl N-(diphenylmethylene)glycinate (1.71 g, 6.40 mmol) in dry THF (10 ml) was added to a stirrred solution of LDA (2M in heptane/TNF/ethylbenzene, 320 ml, 6.40 mmol) in dry THF 910 ml) at xe2x88x9270xc2x0 under nitrogen. After stirring at this temperture for 0.75 h, a solution of 5-benzenesulphonyloxy-2-bromomethylpyridine (2.00 g, 6.01 mmol); [prepared as described by Myers et al, J.O.C. 61, 813 (1996)] in dry THF (10 ml) was added. The reaction mixture was stirred at xe2x88x9270xc2x0 for 1 h then at room temperature for 18 h. The reaction was quenched with water 910 ml) then partitioned between EtOAc (70 ml) and bring (30 ml). The phases were separated and the aqueous phase re-extracted with EtOAc (2xc3x9740 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford the crude product as a dark oil. Chromatography (silica: 60-75% Et2O/Hexane) afforded the title compound as a tan-coloured solid (2.25 g, 72%). xcex4H (CDCl3) 8.02 (1H, d, J 2.8 Hz), 7.72 (2H, d, J 8.0 hz), 7.59 (1H, t, J 8.0 hz), 7.50 (2H, dd, J 8.4 Hz), 7.40-7.27 (8H, m), 7.19 (1H, dd, J 8.5, 2.8 Hz), 7.11 (1H, d, J 8.5 Hz), 6.67 (2H, br d, J 8.0 Hz), 4.50 (1H, dd, J 9.0, 4.6 Hz), 4.25-4.10 (2H, m), 3.50-3.33 (2H, m) and 1.24 (3H, t, J 7.2 Hz), m/z (ES+, 70V) 515 (MH+).
Intermediate 26
Ethyl 2-amino-3-(5-benzenesulphonyloxypyrid-2-yl)propionate
A solution of Intermediate 25 (1.9 g, 3.7 mmol) in 10% aqueous HCl (5 ml) and ethanol (120 ml) was stirred at room temperature for 1.5 h. Most of the solvent was removed in vacuo and the residue partitioned between half-saturated aqueous NaHCO3 (50 ml) and EtOAc (80 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (4xc3x9740 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The obtained yellow oil was chromatographed (silica; EtOAc) to afford the title compound as a coourless oil (1.15 g, 78%). xcex4H (CDCl3) 8.04 (1H, d, J 2.8 Hz), 7.80 (2H, d, J 8.0 Hz), 7.65 (1H, t, J 8 0 Hz), 7.51 (2H, t, J 8.0 Hz), 7.31 (1H, dd, J 8.5, 2.8 Hz), 7.12 (1H, d, J 8.5 Hz), 4.10 (2H, q, J 7.1 Hz), 3.86 (1H, dd, J 7.9, 4.9 Hz), 3.19 (1H, dd, J 14.4, 4.9 Hz), 2.99 (1H, dd, J 14.4, 7.9 Hz), 1.66 (2H, br s) and 1.17 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 351 (MH+).
Intermediate 27
Ethyl-2-(N-t-butyloxycarbonylamino)-3-(5-hydroxypyrid-2-yl)propionate
A solution of Intermediate 26 (3.50 g, 10 mmol) and LiOH/H2O (920 mg, 22 mmol) in dioxan (20 ml) and water (30 ml) was stirred at room temperature for 5 h. The volatiles were removed in vavuo and the residue treated with ethanol (50 ml). HCl gas was bubbled through the mixture for a few minutes and the reaction mixture heated at 50xc2x0 overnight. The volatiles were removed in vacuo and the residue treated with a mixture of di-tert-butyl dicarbonate (1.53 g, 7.0 mmol) and NaHCO3 (3.36 g, 40 mmol) in THF (10 ml) and water (20 ml). After stirring at room temperature for 2 h, additional di-tert-butyldicarbonate (150 mg, 0.7 mmol) was added, the reaction mixture stirred for a further 2 h. The organic volatiles were removed in vacuo and aqueous residue was extracted with EtOAc (2xc3x9775 ml). The combined organic extracts were washed with brine (5 ml), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed (silica, 50% EtOAc/hexane) to afford the title compound as a white solid (1.81 g, 58%), xcex4H (CDCl3; 8:3 ratio of rotamers) 8.14 (0.73H, br s), 8.01 (0.27H, br s), 7.18-7.08 (1H, m), 7.08-6.90 (1H, m), 6.24 (0.27H, br dm J 8.5 Hz), 5.77 (0.73H, br d J 8.5 Hz), 4.64 (0.73H, m), 4.43 (0.27H, m), 4.17 (2H, q, J 7.1 Hz), 3.27-3.14 (2H, m), 1.41 (9H, s and 1.23 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 311 (MH+).
Intermdiate 28
Ethyl-2-(N-t-butyloxycarbonylamino)-3-[5-3-methyl-2,7-naphthyridin-1-yloxy)-pyrid-2-yl]propionate
A mixture of intermediate 27 (1.814 g, 5.85 mmol), Intermediate 17 (0.87 g, 4.87 mmol) and Cs2CO3 (1.73 g, 5.31 mmol) in dry DMF (12 ml) was stirred at 40xc2x0 overnight. The inorganics were removed by filtration with DCM washed and the filtrate evaporated in vacuo to afford a dark oil. Chromatography (silica; 50% EtOAc/Hexane-100% EtOAc) afforded the title compound as a white foam (1.69 g, 77%). xcex4H (CDCl3) 9.71 (1H, s), 8.72 (1H, d, J 5.8 Hz), 8.56 (1H, d, J 2.7 Hz), 7.62 (1H, dd, J 8.4, 2.7 Hz), 7.53 (1H, dd, J 5.8, 0.8 Hz), 7.26 (1H, d, J 8.4 Hz), 7.15 (1H, s), 5.86 (1H, br d, J 9.2 Hz), 4.71 (1H, m), 4.81 (2H, m), 3.45-3.29 (2H, m), 1.46 (9H, s) and 1.27 (3H, t, J 7.2 Hz); m/z (ES+, 70V) 453 (MH+).
Intermediate 29
Ethyl-2-amino-3-[5-(3-methyl-2,7-naphthyridin-1-yloxy)pyrid-2-yl]propionate
Intermediate 28 was dissolved in EtOAc and HCl gas bubbled through for 10 min. Solution neutralised with aqueous NaHCO3 and extracted into EtOAc to quantitatively give the title compound used crude without purification.
Intermediate 30
1,1-Dioxo-tetrahydrothiophen-3-one
Tetrahydrothiophen-3-one (2 g, 19.6 mmol) in CH2C2 (100 ml) at 0xc2x0 was treated with 3-chloroperoxybenzoic acid (9 g) in CH2Cl2 (10 ml). After 3 h the reaction was complete and the solid removed by filtration and the filtrate concentrated in vacuo. The title compound was purified by chromatography (SiO2; EtOAc/hexane 4:1) to give the title compound as a white solid (340 mg; 2.5 mmol; 13%). xcex4H (CDCl3) 3.72 (2H, s), 3.60 (2H, t, J 7.8 Hz), 3.10 (2H, t, J 7.8 Hz). m/z (ES+, 70V) 135 (MH+).